<figure><img src="image_24.png" /><figcaption>**Fig. 21** Schematic representation of Heimdall possible action in astrocytes to maintain their fate. When inhibited through anti-Heimdall or CRISPR-Cas9, the astrocytes neuroprogenitor cells conversion would take place.</figcaption></figure>

part of the kappa light chain. Heimdall like its isoform and the variable heavy chain were secreted during spinal cord injury and thus during inflammation. It is well known that during mammalian neocortical development, neural precursor cells generate neurons first and astrocytes later. The cell fate switch from neurons to astrocytes is a key process generating proper numbers of neurons and astrocytes. Although the intracellular mechanisms regulating this cell fate switch have been well characterized, extracellular regulators are still largely unknown. We thus propose Heimdall as one of these factors. Indeed, Heimdall inhibition triggered elongations as neurites like extension from astrocytes by limiting astrocytes factor expression like GFAP. All neural progenitor factors identified when Heimdall was inhibited and more clearly under LPS stimulation reinforced such hypothesis. The partners identified by immunoprecipitation strengthened the fact that Heimdall controlled the level of transcription factors involved in neuronal pluripotency and secretion of axon guidance factors. In fact, among the factors found in the interactome of Heimdall, IPO13 is known to play a critical role in early embryonic development through nuclear transport of key regulators, such as transcription factors Pax6, Pax3, and ARX [44]. Similarly, we detected erythropoietin-producing hepatocellular (Eph) receptors (EPHA3), which is known to inhibit the Wnt/β-catenin pathway involved in neurogenesis. The Notch signaling pathway has long been known to influence cell fate in the developing nervous system [103]. Inhibition of NOTCH1 signaling resulted in upregulated expression of transcription factors, including NeuroD1, NeuroD2, Pax6, Lmx1a, and Lhx6, in astrocytes and converted them into neurons. It is interesting to note that in vivo, the expression of NOTCH1 was detected in astrocytes, which was significantly increased after SCI. Of note, NOTCH1 was found in the interactome of Heimdall during an inflammation mimicked by LPS treatment. Similarly, NOTCH2 is overexpressed under LPS stimulation and decrease under Heimdall KO. In this condition, HDAC4 which is known to be a key element in astrocytes epigenetic reprogramming [45] was also observed. Altogether, these results showed that Heimdall through its association with NOTCH [1, 2], HDAC4 and IPO13 plays a key role to determine astrocytes fate.

This regulatory role of Heimdall was confirmed by our CRISPR-Cas9 experiment. Indeed, after *Heimdall* KO and LPS stimulation, the axon guidance factors (SLIT3, SEMA3F) have been identified. Moreover, the PTBP factors known to convert astrocytes to neurons is overexpressed when anti-Heimdall is added to the culture medium [104]. Taken together, Heimdall seems to exert with Notch 1 and other fate keepers such as the PTBP factor an important role in gliogenesis and its inhibition switch astrocytes to neurogenesis (Fig. 21).

Moreover, we and others groups have recently demonstrated that according to their nature, neurons differentially expressed at the level of the spinal cord IgGM, IgG2a, IgG2b, and IgG3 isotypes with a transmembrane domain [105, 106]. Previously, another group showed that oligodendrocyte precursors expressed the IgM receptor Fcα/μR (encoded by the *Fcmr* gene) [107] and we established the presence of CD16 and CD32b at the surface of sensory neurons linked to neurite outgrowth [106]. CD97 has been shown to be the receptor of the secreted form of V immunoglobulin Thy-1 suggesting that Heimdall can also have its own receptor. But we cannot exclude that Heimdall can bind the heavy constant chains present at the surface of neurons to form an aberrant antinomy like in cancer [40] but with the ability to form a fragment antigen binding. Interestingly like Heimdall, Thy1 protein has been detected in the hippocampus, followed by the neocortex, cerebellum, and spinal cord. This similarity of localization also suggests an involvement of such Immunoglobulin variable chains in neuritogenesis modulation in course of brain development. Taken together, Heimdall, Thy-1, and neuronal IgGs issued from pseudogenes are novel members of a large family of immunoglobulins. It will be now necessary to determine if these proteins are members of a larger list and if the variability of these chains also occurs in neurons and/or astrocytes as it occurs in B lymphocytes. In this context, we will open the pandorabox of multi-variable brain IgGs and it will be necessary to understand their functions in the crosstalk between neurons and astrocytes.

DATA AVAILABILITY

The data sets and the Perseus result files used for analysis were deposited at the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository with the dataset identifier PXD042754 (Username:
reviewer_pxd042754@ebi.ac.uk; password: awmVOCeV). Heimdall Genbank accessory number: OR085629.

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3. Brunet MA, Leblanc S, Roucou X. Reconsidering proteomic diversity with func-
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4. Samandi S, Roy AV, Delcourt V, Lucier JF, Gagnon J, Beaudoin MC, et al. Deep transcriptome annotation enables the discovery and functional characterization of cryptic small proteins. eLife 2017;6:e27860.

5. Delcourt V, Brunelle M, Roy AV, Jacques JF, Salzet M, Fournier I, et al. The protein coded by a short open reading frame, not by the annotated coding sequence, is the main gene product of the dual-coding gene MIEF1. Mol Cell Proteom MCP. 2018;17:2402–11.

6. Mouilleron H, Delcourt V, Roucou X. Death of a dogma: eukaryotic mRNAs can code for more than one protein. Nucleic Acids Res. 2016;44:14–23.

7. Vanderperre B, Lucier JF, Bissonnette C, Motard J, Tremblay G, Vanderperre S, et al. Direct detection of alternative open reading frames translation products in human significantly expands the proteome. PLoS ONE. 2013;8:e70698.

8. Vanderperre B, Lucier JF, Roucou X. HAItORF: a database of predicted out-of-frame alternative open reading frames in human. Database J Biol Databases Curation 2012;2012:bas025.

9. Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 2015;160:595–606.

10. Thomaidou S, Slieker RC, van der Slik AR, Boom J, Mulder F, Munoz-Garcia A, et al. Long RNA sequencing and ribosome profiling of inflamed β-cells reveal an extensive translatome landscape. Diabetes 2021;70:2299–312.

11. Ouspenskaia T, Law T, Clauser KR, Klaeger S, Sarkizova S, Aguet F, et al. Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer. Nat Biotechnol. 2022;40:209–17.

12. Cardon T, Fournier I, Salzet M. Unveiling a ghost proteome in the glioblastoma non-coding RNAs. Front Cell Dev Biol. 2021;9:703583.

13. Sapkota D, Lake AM, Yang W, Yang C, Wesseling H, Guise A, et al. Cell-type-specific profiling of alternative translation identifies regulated protein isoform variation in the mouse brain. Cell Rep. 2019;26:594–607.e7.

14. De Bellis M, Pisani F, Mola MG, Rosito S, Simone L, Buccoliero C, et al. Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfoot localization, and water transport. Glia 2017;65:790–803.

15. Thomas D, Plant LD, Wilkens CM, McCrossan ZA, Goldstein SAN. Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron 2008;58:859–70.

16. Studtmann K, Olschläger-Schütt J, Buck F, Richter D, Sala C, Bockmann J, et al. A non-canonical initiation site is required for efficient translation of the critically localized Shank1 mRNA. PLoS ONE. 2014;9:e88518.

17. Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science 2001;294:1030–8.

18. Merlini GAL. amyloidosis: from molecular mechanisms to targeted therapies. Hematol Am Soc Hematol Educ Program. 2017;2017:1–12.

19. Magnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EMK, Lindvall O, et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 2014;346:237–41.

20. Cooper A, Berninger B. Gatekeeping astrocyte identity. eLife 2022;11:e80232.

21. Devaux S, Cizkova D, Quanico J, Franck J, Nataf S, Pays L, et al. Proteomic analysis of the spatio-temporal based molecular kinetics of acute spinal cord injury identifies a time- and segment-specific window for effective tissue repair. Mol Cell Proteom MCP. 2016;15:2641–70.

22. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.

23. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res. 2011;10:1794–805.

24. Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res. 2012;40. https://pubmed.ncbi.nlm.nih.gov/22102590/.

25. Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteom MCP. 2014;13:2513–26.

26. Viscaíno JA, Deutsch EW, Wang R, Csordas A, Reisinger F, Rios D, et al. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat Biotechnol. 2014;32:223–6.

27. Viscaíno JA, Côté RG, Csordas A, Dianes JA, Fabregat A, Foster JM, et al. The PRoteomics IDEntifications (PRIDE) database and associated tools: status in 2013. Nucleic Acids Res. 2013;41:D1063–69.

28. Hsu PD, Scott DA, Weinstein JA, Ran FA, Konermann S, Agarwala V, et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol. 2013;31:827–32.

29. Doench JG, Fusi N, Sullender M, Hegde M, Vaimberg EW, Donovan KF, et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat Biotechnol. 2016;34:184–91.

30. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783–4.

31. Ryø LB, Thomsen EA, Mikkelsen JG. Production and validation of lentiviral vectors for CRISPR/Cas9 delivery. Methods Mol Biol Clifton NJ. 2019;1961:93–109.

32. Ke X, Zhang Y, Liu Y, Miao Y, Zheng C, Luo D, et al. A single mutation in the VP1 gene of enterovirus 71 enhances viral binding to heparan sulfate and impairs viral pathogenicity in mice. Viruses 2020;12:883.

33. Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER Suite: protein structure and function prediction. Nat Methods. 2015;12:7–8.

34. Kozakov D, Hall DR, Xia B, Porter KA, Padhorni D, Yueh C, et al. The ClusPro web server for protein-protein docking. Nat Protoc. 2017;12:255–78.

35. Goddard TD, Huang CC, Ferrin TE. Software extensions to UCSF chimera for interactive visualization of large molecular assemblies. Struct Lond Engl 1993. 2005;13:473–82.

36. Devaux S, Cizkova D, Mallah K, Karnoub MA, Laouby Z, Kobeissy F, et al. RhoA inhibitor treatment at acute phase of spinal cord injury may induce neurite outgrowth and synaptogenesis. Mol Cell Proteom MCP. 2017;16:1394–415.

37. Itoh N, Itoh Y, Tassoni A, Ren E, Kaito M, Ohno A, et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc Natl Acad Sci USA. 2018;115:E302–9.

38. Shigemitsu Y, Hiroaki H. Common molecular pathogenesis of disease-related intrinsically disordered proteins revealed by NMR analysis. J Biochem. 2018;163:11–8.

39. Oldfield CJ, Dunker AK. Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem. 2014;83:553–84.

40. Hu D, Duan Z, Li M, Jiang Y, Liu H, Zheng H, et al. Heterogeneity of aberrant immunoglobulin expression in cancer cells. Cell Mol Immunol. 2011;8:479–85.

41. Holsapple MP, West LJ, Landreth KS. Species comparison of anatomical and functional immune system development. Birth Defects Res B Dev Reprod Toxicol. 2003;68:321–34.

42. Winkler TH, Mårtensson IL. The role of the pre-B cell receptor in B cell development, repertoire selection, and tolerance. Front Immunol. 2018;9:2423.

43. Fang Y, Cho KS, Tchedre K, Lee SW, Guo C, Kinouchi H, et al. Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency. Stem Cells. 2013;31:349–59.

44. Gajewska KA, Haynes JM, Jans DA. Nuclear transporter IPO13 is central to efficient neuronal differential differentiation. Cells 2022;11:1904.

45. Vasan L, Park E, David LA, Fleming T, Schuurmans C. Direct neuronal reprogramming: bridging the gap between basic science and clinical application. Front Cell Dev Biol. 2021;9:e681087.

46. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Prim. 2017;3:17013.

47. Wang X, Su B, Liu W, He X, Gao Y, Castellani RJ, et al. DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson's disease. Aging Cell. 2011;10:807–23.

48. Hoekstra JG, Cook TJ, Stewart T, Mattison H, Dreisbach MT, Hoffer ZS, et al. Astrocytic dynamin-like protein 1 regulates neuronal protection against excitotoxicity in Parkinson disease. Am J Pathol. 2015;185:536–49.

49. Menegon A, Board PG, Blackburn AC, Mellick GD, Le Couteur DG. Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet Lond Engl. 1998;352:1344–6.

50. Bi M, Du X, Jiao Q, Chen X, Jiang H. Expanding the role of proteasome home-
ostasis in Parkinson's disease: beyond protein breakdown. Cell Death Dis.
2021;12:154.

51. Gazzin S, Vitek L, Watchko J, Shapiro SM, Tirbelli C. A novel perspective on the biology of bilirubin in health and disease. Trends Mol Med. 2016;22:758–68.

52. Lakshmikuttyamma A, Selvakumar P, Tuchek J, Sharma RK. Myristoyltransferase and calcineurin: novel molecular therapeutic target for epilepsy. Prog Neurobiol. 2008;84:77–84.

53. McNeill J, Rudyk C, Hildebrand ME, Salmaso N. Ion channels and electro-
physiological properties of astrocytes: implications for emergent stimulation
technologies. Front Cell Neurosci. 2021;15:644126.
reviewer_pxd042754@ebi.ac.uk; password: awmVOCeV). Heimdall Genbank accessory number: OR085629.

REFERENCES

1. UniProt Consortium. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 2021;49:D480–9.

2. Cardon T, Fournier I, Salzet M. Shedding light on the ghost proteome. Trends Biochem Sci. 2021;46:239–50.

3. Brunet MA, Leblanc S, Roucou X. Reconsidering proteomic diversity with func-
tional investigation of small ORFs and alternative ORFs. Exp Cell Res.
2020;393:112057.

4. Samandi S, Roy AV, Delcourt V, Lucier JF, Gagnon J, Beaudoin MC, et al. Deep transcriptome annotation enables the discovery and functional characterization of cryptic small proteins. eLife 2017;6:e27860.

5. Delcourt V, Brunelle M, Roy AV, Jacques JF, Salzet M, Fournier I, et al. The protein coded by a short open reading frame, not by the annotated coding sequence, is the main gene product of the dual-coding gene MIEF1. Mol Cell Proteom MCP. 2018;17:2402–11.

6. Mouilleron H, Delcourt V, Roucou X. Death of a dogma: eukaryotic mRNAs can code for more than one protein. Nucleic Acids Res. 2016;44:14–23.

7. Vanderperre B, Lucier JF, Bissonnette C, Motard J, Tremblay G, Vanderperre S, et al. Direct detection of alternative open reading frames translation products in human significantly expands the proteome. PLoS ONE. 2013;8:e70698.

8. Vanderperre B, Lucier JF, Roucou X. HAItORF: a database of predicted out-of-frame alternative open reading frames in human. Database J Biol Databases Curation 2012;2012:bas025.

9. Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 2015;160:595–606.

10. Thomaidou S, Slieker RC, van der Slik AR, Boom J, Mulder F, Munoz-Garcia A, et al. Long RNA sequencing and ribosome profiling of inflamed β-cells reveal an extensive translatome landscape. Diabetes 2021;70:2299–312.

11. Ouspenskaia T, Law T, Clauser KR, Klaeger S, Sarkizova S, Aguet F, et al. Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer. Nat Biotechnol. 2022;40:209–17.

12. Cardon T, Fournier I, Salzet M. Unveiling a ghost proteome in the glioblastoma non-coding RNAs. Front Cell Dev Biol. 2021;9:703583.

13. Sapkota D, Lake AM, Yang W, Yang C, Wesseling H, Guise A, et al. Cell-type-specific profiling of alternative translation identifies regulated protein isoform variation in the mouse brain. Cell Rep. 2019;26:594–607.e7.

14. De Bellis M, Pisani F, Mola MG, Rosito S, Simone L, Buccoliero C, et al. Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfoot localization, and water transport. Glia 2017;65:790–803.

15. Thomas D, Plant LD, Wilkens CM, McCrossan ZA, Goldstein SAN. Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron 2008;58:859–70.

16. Studtmann K, Olschläger-Schütt J, Buck F, Richter D, Sala C, Bockmann J, et al. A non-canonical initiation site is required for efficient translation of the critically localized Shank1 mRNA. PLoS ONE. 2014;9:e88518.

17. Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science 2001;294:1030–8.

18. Merlini GAL. amyloidosis: from molecular mechanisms to targeted therapies. Hematol Am Soc Hematol Educ Program. 2017;2017:1–12.

19. Magnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EMK, Lindvall O, et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 2014;346:237–41.

20. Cooper A, Berninger B. Gatekeeping astrocyte identity. eLife 2022;11:e80232.

21. Devaux S, Cizkova D, Quanico J, Franck J, Nataf S, Pays L, et al. Proteomic analysis of the spatio-temporal based molecular kinetics of acute spinal cord injury identifies a time- and segment-specific window for effective tissue repair. Mol Cell Proteom MCP. 2016;15:2641–70.

22. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.

23. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res. 2011;10:1794–805.

24. Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res. 2012;40. https://pubmed.ncbi.nlm.nih.gov/22102590/.

25. Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteom MCP. 2014;13:2513–26.

26. Viscaíno JA, Deutsch EW, Wang R, Csordas A, Reisinger F, Rios D, et al. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat Biotechnol. 2014;32:223–6.

27. Viscaíno JA, Côté RG, Csordas A, Dianes JA, Fabregat A, Foster JM, et al. The PRoteomics IDEntifications (PRIDE) database and associated tools: status in 2013. Nucleic Acids Res. 2013;41:D1063–69.

28. Hsu PD, Scott DA, Weinstein JA, Ran FA, Konermann S, Agarwala V, et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol. 2013;31:827–32.

29. Doench JG, Fusi N, Sullender M, Hegde M, Vaimberg EW, Donovan KF, et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat Biotechnol. 2016;34:184–91.

30. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783–4.

31. Ryø LB, Thomsen EA, Mikkelsen JG. Production and validation of lentiviral vectors for CRISPR/Cas9 delivery. Methods Mol Biol Clifton NJ. 2019;1961:93–109.

32. Ke X, Zhang Y, Liu Y, Miao Y, Zheng C, Luo D, et al. A single mutation in the VP1 gene of enterovirus 71 enhances viral binding to heparan sulfate and impairs viral pathogenicity in mice. Viruses 2020;12:883.

33. Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER Suite: protein structure and function prediction. Nat Methods. 2015;12:7–8.

34. Kozakov D, Hall DR, Xia B, Porter KA, Padhorni D, Yueh C, et al. The ClusPro web server for protein-protein docking. Nat Protoc. 2017;12:255–78.

35. Goddard TD, Huang CC, Ferrin TE. Software extensions to UCSF chimera for interactive visualization of large molecular assemblies. Struct Lond Engl 1993. 2005;13:473–82.

36. Devaux S, Cizkova D, Mallah K, Karnoub MA, Laouby Z, Kobeissy F, et al. RhoA inhibitor treatment at acute phase of spinal cord injury may induce neurite outgrowth and synaptogenesis. Mol Cell Proteom MCP. 2017;16:1394–415.

37. Itoh N, Itoh Y, Tassoni A, Ren E, Kaito M, Ohno A, et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc Natl Acad Sci USA. 2018;115:E302–9.

38. Shigemitsu Y, Hiroaki H. Common molecular pathogenesis of disease-related intrinsically disordered proteins revealed by NMR analysis. J Biochem. 2018;163:11–8.

39. Oldfield CJ, Dunker AK. Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem. 2014;83:553–84.

40. Hu D, Duan Z, Li M, Jiang Y, Liu H, Zheng H, et al. Heterogeneity of aberrant immunoglobulin expression in cancer cells. Cell Mol Immunol. 2011;8:479–85.

41. Holsapple MP, West LJ, Landreth KS. Species comparison of anatomical and functional immune system development. Birth Defects Res B Dev Reprod Toxicol. 2003;68:321–34.

42. Winkler TH, Mårtensson IL. The role of the pre-B cell receptor in B cell development, repertoire selection, and tolerance. Front Immunol. 2018;9:2423.

43. Fang Y, Cho KS, Tchedre K, Lee SW, Guo C, Kinouchi H, et al. Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency. Stem Cells. 2013;31:349–59.

44. Gajewska KA, Haynes JM, Jans DA. Nuclear transporter IPO13 is central to efficient neuronal differential differentiation. Cells 2022;11:1904.

45. Vasan L, Park E, David LA, Fleming T, Schuurmans C. Direct neuronal reprogramming: bridging the gap between basic science and clinical application. Front Cell Dev Biol. 2021;9:e681087.

46. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Prim. 2017;3:17013.

47. Wang X, Su B, Liu W, He X, Gao Y, Castellani RJ, et al. DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson's disease. Aging Cell. 2011;10:807–23.

48. Hoekstra JG, Cook TJ, Stewart T, Mattison H, Dreisbach MT, Hoffer ZS, et al. Astrocytic dynamin-like protein 1 regulates neuronal protection against excitotoxicity in Parkinson disease. Am J Pathol. 2015;185:536–49.

49. Menegon A, Board PG, Blackburn AC, Mellick GD, Le Couteur DG. Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet Lond Engl. 1998;352:1344–6.

50. Bi M, Du X, Jiao Q, Chen X, Jiang H. Expanding the role of proteasome home-
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2021;12:154.

51. Gazzin S, Vitek L, Watchko J, Shapiro SM, Tirbelli C. A novel perspective on the biology of bilirubin in health and disease. Trends Mol Med. 2016;22:758–68.

52. Lakshmikuttyamma A, Selvakumar P, Tuchek J, Sharma RK. Myristoyltransferase and calcineurin: novel molecular therapeutic target for epilepsy. Prog Neurobiol. 2008;84:77–84.

53. McNeill J, Rudyk C, Hildebrand ME, Salmaso N. Ion channels and electro-
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72. Limoni G, Niquille M. Semaphorins and Plexins in central nervous system patterning: the key to it all? *Curr Opin Neurobiol.* 2021;66:224–32.

73. Funa K, Sasahara M. The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. *J NeurolImmune Pharm.* 2014;9:168–81.

74. Nakamura F, Ohshima T, Goshima Y. Collapsin response mediator proteins: their biological functions and pathophysiology in neuronal development and regeneration. *Front Cell Neurosci.* 2020;14:188.

75. Brick RM, Sun AX, Tuan RS. Neurotrophically induced mesenchymal progenitor cells derived from induced pluripotent stem cells enhance neuritogenesis via neurotrophin and cytokine production. *Stem Cells Transl Med.* 2018;7:45–58.

76. Sabelström H, Petri R, Shchors K, Jandial R, Schmidt C, Sacheva R, et al. Driving neuronal differentiation through reversal of an ERK1/2-miR-124-SOX9 axis abrogates glioblastoma aggressiveness. *Cell Rep.* 2019;28:2064–79.e11.

77. Nabeka H, Saito S, Li X, Shimokawa T, Khan MSI, Yamamiya K, et al. Interneurons secrete prosaposin, a neurotrophic factor, to attenuate kainic acid-induced neurotoxicity. *IBRO Rep.* 2017;3:17–32.

78. Jaafar C, Omais S, Al Lafi S, El Jamal N, Noubani M, Skaf L, et al. Role of Rb during neurogenesis and axonal guidance in the developing olfactory system. *Front Mol Neurosci.* 2016;9:81.

79. Lu Z, Kipnis J. Thrombospondin 1—a key astrocyte-derived neurogenic factor. *FASEB J Publ Fed Am Soc Exp Biol.* 2010;24:1925–34.

80. Shi J, Wei L. Rho kinases in embryonic development and stem cell research. *Arch Immunol Ther Exp.* 2022;70:4.

81. Tchorz JS, Tome M, Cloëtta D, Sivasankaran B, Grzmil M, Huber RM, et al. Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry. *Cell Death Dis.* 2012;3:e325.

82. Lin L, Isacson O. Axonal growth regulation of fetal and embryonic stem cell-derived dopaminergic neurons by Netrin-1 and Slits. *Stem Cells.* 2006;24:2504–13.

83. Ng T, Ryu JR, Sohn JH, Tan T, Song H, Ming GL, et al. Class 3 semaphorin mediates dendrite growth in adult newborn neurons through Cdk5/FAK pathway. *PLoS ONE.* 2013;8:e65572.

84. Yi JJ, Barnes AP, Hand R, Polleux F, Ehlers MD. TGF-beta signaling specifies axons during brain development. *Cell* 2010;142:144–57.

85. Tsai NP, Tsui YC, Pintar JE, Loh HH, Wei LN. Kappa opioid receptor contributes to EGF-stimulated neurite extension in development. *Proc Natl Acad Sci USA.* 2010;107:3216–21.

86. Fu C, Xu J, Cheng W, Rojas T, Chin AC, Snowman AM, et al. Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase. *Proc Natl Acad Sci USA.* 2017;114:2036–41.

87. Lin L, Lo LHY, Lyu Q, Lai KO. Determination of dendritic spine morphology by the striatin scaffold protein STRN4 through interaction with the phosphatase PP2A. *J Biol Chem.* 2017;292:9451–64.

88. Di Domenico M, Jokwitz M, Witke W, Pilo, Boyl P. Specificity and redundancy of profilin 1 and 2 function in brain development and neuronal structure. *Cells* 2021;10:2310.

89. White JK, Auerbach W, Duyao MP, Vonsattel JP, Gusella JF, Joyner AL, et al. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. *Nat Genet.* 1997;17:404–10.

90. Dugan LL, Kim JS, Zhang Y, Bart RD, Sun Y, Holtzman DM, et al. Differential effects of cAMP in neurons and astrocytes. *Role of B-raf. J Biol Chem.* 1999;274:25842–8.

91. Amodeo VAD, Betts J, Bartesaghi S, Zhang Y, Richard-Londt A, et al. A PML/slit axis controls physiological cell migration and cancer invasion in the CNS. *Cell Rep.* 2017;20:411–26.

92. Yamada T, Urano-Tashiro Y, Hashi Y, Sakumoto M, Akiyama H, Tashiro F. The U-box-type ubiquitin ligase PRP19β regulates astrocyte differentiation via ubiquitination of PTP1B. *Brain Res.* 2013;1524:12–25.

93. Pontis S, Palese F, Summa M, Realini N, Lanfranco M, De Mei C, et al. N-Acylethanolamine Acid Amidase contributes to disease progression in a mouse model of multiple sclerosis. *Pharm Res.* 2020;160:105064.

94. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. *Signal Transduct Target Ther.* 2021;6:402.

95. Roberts JM, Ennajdaoui H, Edmondson C, Wirth B, Sanford JR, Chen B. Splicing factor TRA2B is required for neural progenitor survival. *J Comp Neurol.* 2014;522:372–92.

96. Yang L, Tao T, Wang Y, Bao Z, He X, Cui G. Knocking down the expression of TRA2β inhibits the proliferation and migration of human glioma cells. *Pathol Res Pr.* 2015;211:731–9.

97. Shirai K, Shimada T, Yoshida H, Hayakari R, Matsumiya T, Tanji K, et al. Interferon (IFN)-induced protein 35 (IFI35) negatively regulates IFN-β-phosphorylated STAT1-RIG-I-CXCL10/CCL5 axis in U373MG astrocytoma cells treated with polyinosinic-polycytidylic acid. *Brain Res.* 2017;1658:60–7.

98. Häusl AS, Brix LM, Hartmann J, Pöhlmann ML, Lopez JP, Menegaz D, et al. The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. *Mol Psychiatry.* 2021;26:3060–76.

99. Kemshead JT, Ritter MA, Cotmore SF, Greaves MF. Human Thy-1: expression on the cell surface of neuronal and glial cells. *Brain Res.* 1982;236:451–61.

100. Herrera-Molina R, Frischknecht R, Maldonado H, Seidenbecher CI, Gundelfinger ED, Hetz C, et al. Astrocytic αVβ3 integrin inhibits neurite outgrowth and promotes retraction of neuronal processes by clustering Thy-1. *PLoS ONE.* 2012;7:e34295.

101. Lagos-Cabrê R, Alvarez A, Kong M, Burgos-Bravo F, Cárdenas A, Rojas-Mancilla E, et al. Vβ3 Integrin regulates astrocyte reactivity. *J Neuroinflammation.* 2017;14:194.

102. Chen CH, Wang SM, Yang SH, Jeng CJ. Role of Thy-1 in in vivo and in vitro neural development and regeneration of dorsal root ganglionic neurons. *J Cell Biochem.* 2005;94:684–94.

103. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. *Annu Rev Neurosci.* 2002;25:471–90.

104. Contardo M, De Gioia R, Gagliardi D, Comi GP, Ottoboni L, Nizzardo M, et al. Targeting PTB for glia-to-neuron reprogramming in vitro and in vivo for therapeutic development in neurological diseases. *Biomedicines* 2022;10:399.

105. Scheurer L, Das Gupta RR, Saebisch A, Grampp T, Benke D, Zeilhofer HU, et al. Expression of immunoglobulin constant domain genes in neurons of the mouse central nervous system. *Life Sci Alliance.* 2021;4:e202101154.
54. Bolton S, Greenwood K, Hamilton N, Butt AM. Regulation of the astrocyte resting membrane potential by cyclic AMP and protein kinase A. *Glia* 2006;54:316-28.

55. Sakakibara S, Nakamura Y, Satoh H, Okano H. RNA-binding protein Musashi2: developmentally regulated expression in neural precursor cells and subpopulations of neurons in mammalian CNS. *J Neurosci* J Soc Neurosci. 2001;21:8091-107.

56. Zhang C, Li D, Ma Y, Yan J, Yang B, Li P, et al. Role of spastin and protrudin in neurite outgrowth. *J Cell Biochem.* 2012;113:2296-307.

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58. Schmid RS, Pruitt WM, Maness PFA. MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis. *J Neurosci* J Soc Neurosci. 2000;20:4177-88.

59. Li L, Liu QR, Xiong XX, Liu JM, Lai XJ, Cheng C, et al. Neuroglobin promotes neurite outgrowth via differential binding to PTEN and Akt. *Mol Neurobiol.* 2014;49:149-62.

60. Jin EJ, Ko HR, Hwang I, Kim BS, Choi JY, Park KW, et al. Akt regulates neurite growth by phosphorylation-dependent inhibition of radixin proteasomal degradation. *Sci Rep.* 2018;8:2557.

61. Crespi A, Ferrari I, Lonati P, Disanza A, Fornasari D, Scita G, et al. LIN7 regulates the filopodium- and neurite-promoting activity of IRSp53. *J Cell Sci.* 2012;125:4543-54.

62. Zuo YC, Xiong NX, Shen JY, Yu H, Huang YZ, Zhao HY. MARK2 rescues nogo-66-induced inhibition of neurite outgrowth via regulating microtubule-associated proteins in neurons in vitro. *Neurochem Res.* 2016;41:2958-68.

63. Doyle KP, Cekanaviciute E, Mamer LE, Buckwalter MS. TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. *J Neuroinflammation.* 2010;7:62.

64. Meyers EA, Kessler JA. TGF-β family signaling in neural and neuronal differentiation, development, and function. *Cold Spring Harb Perspect Biol.* 2017;9:a022244.

65. Lai YJ, Li MY, Yang CY, Huang KH, Tsai JC, Wang TW. TRIP6 regulates neural stem cell maintenance in the postnatal mammalian subventricular zone. *Dev Dyn Publ Am Assoc Anat.* 2014;243:1130-42.

66. Masserdotti G, Gillotin S, Sutor B, Drechsel D, Irmler M, Jørgensen HF, et al. Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes. *Cell Stem Cell.* 2015;17:74-88.

67. Apicelli AJ, Uhlmann EJ, Baldwin RL, Ding H, Nagy A, Guha A, et al. Role of the Rap1 GTPase in astrocyte growth regulation. *Glia* 2003;42:225-34.

68. Cloëtta D, Thomanetz V, Baranek C, Lustenberger RM, Lin S, Oliveri F, et al. Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis. *J Neurosci.* 2013;33. https://pubmed.ncbi.nlm.nih.gov/23637172/.

69. Addis RC, Hsu FC, Wright RL, Dichter MA, Coulter DA, Gearhart JD. Efficient conversion of astrocytes to functional midbrain dopaminergic neurons using a single polycistronic vector. *PLoS ONE.* 2011;6. https://pubmed.ncbi.nlm.nih.gov/22174877/.

70. Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, et al. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. *Nat Cell Biol.* 2013;15. https://pubmed.ncbi.nlm.nih.gov/24056302/.

71. Hillen AEJ, Burbach JPH, Hol EM. Cell adhesion and matricellular support by astrocytes of the tripartite synapse. *Prog Neurobiol.* 2018;165-167:66-86.

72. Limoni G, Niquille M. Semaphorins and Plexins in central nervous system patterning: the key to it all? *Curr Opin Neurobiol.* 2021;66:224-32.

73. Funa K, Sasahara M. The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. *J NeurolImmune Pharm.* 2014;9:168-81.

74. Nakamura F, Ohshima T, Goshima Y. Collapsin response mediator proteins: their biological functions and pathophysiology in neuronal development and regeneration. *Front Cell Neurosci.* 2020;14:188.

75. Brick RM, Sun AX, Tuan RS. Neurotrophically induced mesenchymal progenitor cells derived from induced pluripotent stem cells enhance neuritogenesis via neurotrophin and cytokine production. *Stem Cells Transl Med.* 2018;7:45-58.

76. Sabelström H, Petri R, Shchors K, Jandial R, Schmidt C, Sacheva R, et al. Driving neuronal differentiation through reversal of an ERK1/2-miR-124-SOX9 axis abrogates glioblastoma aggressiveness. *Cell Rep.* 2019;28:2064-79.e11.

77. Nabeka H, Saito S, Li X, Shimokawa T, Khan MSI, Yamamiya K, et al. Interneurons secrete prosaposin, a neurotrophic factor, to attenuate kainic acid-induced neurotoxicity. *IBRO Rep.* 2017;3:17-32.

78. Jaafar C, Omais S, Al Lafi S, El Jamal N, Noubani M, Skaf L, et al. Role of Rb during neurogenesis and axonal guidance in the developing olfactory system. *Front Mol Neurosci.* 2016;9:81.

79. Lu Z, Kipnis J. Thrombospondin 1—a key astrocyte-derived neurogenic factor. *FASEB J Publ Fed Am Soc Exp Biol.* 2010;24:1925-34.

80. Shi J, Wei L. Rho kinases in embryonic development and stem cell research. *Arch Immunol Ther Exp.* 2022;70:4.

81. Tchorz JS, Tome M, Cloëtta D, Sivasankaran B, Grzmil M, Huber RM, et al. Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry. *Cell Death Dis.* 2012;3:e325.

82. Lin L, Isacson O. Axonal growth regulation of fetal and embryonic stem cell-derived dopaminergic neurons by Netrin-1 and Slits. *Stem Cells.* 2006;24:2504-13.

83. Ng T, Ryu JR, Sohn JH, Tan T, Song H, Ming GL, et al. Class 3 semaphorin mediates dendrite growth in adult newborn neurons through Cdk5/FAK pathway. *PLoS ONE.* 2013;8:e65572.

84. Yi JJ, Barnes AP, Hand R, Polleux F, Ehlers MD. TGF-beta signaling specifies axons during brain development. *Cell* 2010;142:144-57.

85. Tsai NP, Tsui YC, Pintar JE, Loh HH, Wei LN. Kappa opioid receptor contributes to EGF-stimulated neurite extension in development. *Proc Natl Acad Sci USA.* 2010;107:3216-21.

86. Fu C, Xu J, Cheng W, Rojas T, Chin AC, Snowman AM, et al. Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase. *Proc Natl Acad Sci USA.* 2017;114:2036-41.

87. Lin L, Lo LHY, Lyu Q, Lai KO. Determination of dendritic spine morphology by the striatin scaffold protein STRN4 through interaction with the phosphatase PP2A. *J Biol Chem.* 2017;292:9451-64.

88. Di Domenico M, Jokwitz M, Witke W, Pilo, Boyl P. Specificity and redundancy of profilin 1 and 2 function in brain development and neuronal structure. *Cells* 2021;10:2310.

89. White JK, Auerbach W, Duyao MP, Vonsattel JP, Gusella JF, Joyner AL, et al. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. *Nat Genet.* 1997;17:404-10.

90. Dugan LL, Kim JS, Zhang Y, Bart RD, Sun Y, Holtzman DM, et al. Differential effects of cAMP in neurons and astrocytes. *Role of B-raf. J Biol Chem.* 1999;274:25842-8.

91. Amodeo VAD, Betts J, Bartesaghi S, Zhang Y, Richard-Londt A, et al. A PML/slit axis controls physiological cell migration and cancer invasion in the CNS. *Cell Rep.* 2017;20:411-26.

92. Yamada T, Urano-Tashiro Y, Hashi Y, Sakumoto M, Akiyama H, Tashiro F. The U-box-type ubiquitin ligase PRP19β regulates astrocyte differentiation via ubiquitination of PTP1B. *Brain Res.* 2013;1524:12-25.

93. Pontis S, Palese F, Summa M, Realini N, Lanfranco M, De Mei C, et al. N-Acylethanolamine Acid Amidase contributes to disease progression in a mouse model of multiple sclerosis. *Pharm Res.* 2020;160:105064.

94. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. *Signal Transduct Target Ther.* 2021;6:402.

95. Roberts JM, Ennajdaoui H, Edmondson C, Wirth B, Sanford JR, Chen B. Splicing factor TRA2B is required for neural progenitor survival. *J Comp Neurol.* 2014;522:372-92.

96. Yang L, Tao T, Wang Y, Bao Z, He X, Cui G. Knocking down the expression of TRA2β inhibits the proliferation and migration of human glioma cells. *Pathol Res Pr.* 2015;211:731-9.

97. Shirai K, Shimada T, Yoshida H, Hayakari R, Matsumiya T, Tanji K, et al. Interferon (IFN)-induced protein 35 (IFI35) negatively regulates IFN-β-phosphorylated STAT1-RIG-I-CXCL10/CCL5 axis in U373MG astrocytoma cells treated with polyinosinic-polycytidylic acid. *Brain Res.* 2017;1658:60-7.

98. Häusl AS, Brix LM, Hartmann J, Pöhlmann ML, Lopez JP, Menegaz D, et al. The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. *Mol Psychiatry.* 2021;26:3060-76.

99. Kemshead JT, Ritter MA, Cotmore SF, Greaves MF. Human Thy-1: expression on the cell surface of neuronal and glial cells. *Brain Res.* 1982;236:451-61.

100. Herrera-Molina R, Frischknecht R, Maldonado H, Seidenbecher CI, Gundelfinger ED, Hetz C, et al. Astrocytic αVβ3 integrin inhibits neurite outgrowth and promotes retraction of neuronal processes by clustering Thy-1. *PLoS ONE.* 2012;7:e34295.

101. Lagos-Cabrê R, Alvarez A, Kong M, Burgos-Bravo F, Cárdenas A, Rojas-Mancilla E, et al. Vβ3 Integrin regulates astrocyte reactivity. *J Neuroinflammation.* 2017;14:194.

102. Chen CH, Wang SM, Yang SH, Jeng CJ. Role of Thy-1 in in vivo and in vitro neural development and regeneration of dorsal root ganglionic neurons. *J Cell Biochem.* 2005;94:684-94.

103. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. *Annu Rev Neurosci.* 2002;25:471-90.

104. Contardo M, De Gioia R, Gagliardi D, Comi GP, Ottoboni L, Nizzardo M, et al. Targeting PTB for glia-to-neuron reprogramming in vitro and in vivo for therapeutic development in neurological diseases. *Biomedicines* 2022;10:399.

105. Scheurer L, Das Gupta RR, Saebisch A, Grampp T, Benke D, Zeilhofer HU, et al. Expression of immunoglobulin constant domain genes in neurons of the mouse central nervous system. *Life Sci Alliance.* 2021;4:e202101154.
106. Capuz A, Karnoub MA, Osien S, Rose M, Mériaux C, Fournier I, et al. The antibody dependant neurite outgrowth modulation response involvement in spinal cord injury. Front Immunol. 2022;13:882830.

107. Nakahara J, Tan-Takeuchi K, Seiwa C, Gotoh M, Kaifu T, Ujike A, et al. Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation. Dev Cell. 2003;4:841-52.

## ACKNOWLEDGEMENTS

This research was supported by funding from ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (MESRI), Institut National de la Santé et de la Recherche Médicale (Inserm), I-SITE ULNE (Nobody Project), VEGA 1/0376/20 (DC) and APVV 19-0193 (DC). Regional council Hauts de France, and Université de Lille. The authors would like to thank Zarah Laouby, and Estelle Laurent for their contribution to this manuscript.

## AUTHOR CONTRIBUTIONS

Conceptualization: MS; methodology: OS, AC, TC, SA, MD, ARR, MAK, MT, DC, IF, FR, and MS; software: MS and TC; validation: TC, DC, FR, and MS; formal analysis: MS, FR, and DC. Investigation: FR, DC, and MS; resources: DC, IF, MT, DD, and MS; data curation: MS, FR, AC, OS, and TC; writing—original draft: MS; writing—review and editing: IF, DC, FR, and MS; supervision: FR, DC, and MS; project administration: DD and MS; funding acquisition: DC, IF, MT, DD, and MS.

## COMPETING INTERESTS

The authors declare no competing interests.

## ADDITIONAL INFORMATION

**Supplementary information** The online version contains supplementary material available at https://doi.org/10.1038/s41419-023-06037-y.

**Correspondence** and requests for materials should be addressed to Franck Rodet or Michel Salzet.

**Reprints and permission information** is available at http://www.nature.com/reprints

**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_25.png" /></figure>

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2023, corrected publication 2023
106. Capuz A, Karnoub MA, Osien S, Rose M, Mériaux C, Fournier I, et al. The antibody dependant neurite outgrowth modulation response involvement in spinal cord injury. Front Immunol. 2022;13:882830.

107. Nakahara J, Tan-Takeuchi K, Seiwa C, Gotoh M, Kaifu T, Ujike A, et al. Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation. Dev Cell. 2003;4:841-52.

## ACKNOWLEDGEMENTS

This research was supported by funding from ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (MESRI), Institut National de la Santé et de la Recherche Médicale (Inserm), I-SITE ULNE (Nobody Project), VEGA 1/0376/20 (DC) and APVV 19-0193 (DC). Regional council Hauts de France, and Université de Lille. The authors would like to thank Zarah Laouby, and Estelle Laurent for their contribution to this manuscript.

## AUTHOR CONTRIBUTIONS

Conceptualization: MS; methodology: OS, AC, TC, SA, MD, ARR, MAK, MT, DC, IF, FR, and MS; software: MS and TC; validation: TC, DC, FR, and MS; formal analysis: MS, FR, and DC. Investigation: FR, DC, and MS; resources: DC, IF, MT, DD, and MS; data curation: MS, FR, AC, OS, and TC; writing—original draft: MS; writing—review and editing: IF, DC, FR, and MS; supervision: FR, DC, and MS; project administration: DD and MS; funding acquisition: DC, IF, MT, DD, and MS.

## COMPETING INTERESTS

The authors declare no competing interests.

## ADDITIONAL INFORMATION

**Supplementary information** The online version contains supplementary material available at https://doi.org/10.1038/s41419-023-06037-y.

**Correspondence** and requests for materials should be addressed to Franck Rodet or Michel Salzet.

**Reprints and permission information** is available at http://www.nature.com/reprints

**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_25.png" /></figure>

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2023, corrected publication 2023