Molecular regulation of somatosensory neuron development

The somatosensory system of vertebrates perceives and transmits a variety of information from both external and internal environments to the central nervous system where an integrated response is established leading to adaptive outcome. Specific classes of sensory neurons convey the information consisting of touch, muscle stretch, temperature, itch, and pain. Each type of sensory neuron expresses a group of specific markers or proteins in order to perform a specialized function. However, the mechanisms that ensure the acquisition of various molecular traits by somatosensory neurons during development is still not fully understood. This doctoral thesis explores several early developmental events for different types of somatosensory neurons at molecular and cellular levels in order to reduce the gap of knowledge in this field. In Paper I and II, we investigated the neuronal specification of nociceptive neurons, which were derived from specific waves of neurogenesis. We found that PRDM12, an epigenetic regulator, was necessary for the entire nociceptive lineage to develop. In the absence of PRDM12, neural crest precursors failed to generate all of the nociceptive neurons. We also found that the key transcription factor RUNX1, which plays an important role in the diversification of nociceptive neurons, was induced by factors released by early born neurons, emphasizing the important influence of the environment created by early postmitotic neurons on the fate of later born neurons. In Paper III, we proposed a new cell selection model in the early cell death of sensory neurons using the proprioceptive neurons population as a model system. The canonical neurotrophic theory suggests similarity of neurons when competing for target-derived neurotrophins for their survival. However, our data showed that early proprioceptive neurons exhibit a molecular heterogeneity code leading to different capacities to survive already before the cell death period. Further, this capacity was intrinsically regulated by the transcription factor RUNX3 whose expression was defined by the surrounding morphogen retinoic acid. Finally, in Paper IV, we showed that the transcription factor RUNX3 controls the axonal growth rate of developing sensory neurons in a strict temporal and spatial manner. Taking advantage of both chicken embryos and mouse genetics, we observed that the difference in peripheral nerve growth at different axial levels was encoded by RUNX3 expression. In summary, the data collected in this thesis describes several new insights into the molecular regulation during the step-wise development of somatosensory neurons, including neurogenesis, neuronal specification, early cell death, and axonal growth. This knowledge will help us to the better understanding of the development of the somatosensory system as well as provide new knowledge that might help improving approaches of treatment for patients with somatosensory disorders such as congenital insensitivity to pain. LIST OF SCIENTIFIC PAPERS I. Wang Y*, Bartesaghi L*, Fontanet P, Wanderoy S, Berger F, Wu H, Akkuratova N, Bouçanova F, Médard JJ, Landy MA, Zhang M, Harrer P, Stendel C, Stucka R, Dusl M, Kastriti ME, Croci L, Lai HC, Consalez GG, Pattyn A, Ernfors P, Senderek J, Adameyko I, Chrast R, Hadjab S, Lallemend F. PRDM12 is required for initiation of the nociceptive neuron lineage during neurogenesis. Under revision in Cell Reports. II. Hadjab S, Franck MC, Wang Y, Sterzenbach U, Sharma A, Ernfors P, Lallemend F. (2013). A local source of FGF initiates development of the unmyelinated lineage of sensory neurons. Journal of Neuroscience, 2013 Nov 6; 33(45):17656-66. III. Wang Y*, Hadjab S*, Wu H, Codeluppi S, Sharma A, Xue-Franzén Y, Niederreither K, Silva FD, Comai G, Petitpré C, Agirman G, Palumberi D, Linnarsson S, Moqrich A, Schedl A, Lallemend F. A cell fitness selection model for neuronal survival during the development. Under revision in Nature Communications. IV. Lallemend F, Sterzenbach U, Hadjab-Lallemend S, Aquino JB, CasteloBranco G, Sinha I, Villaescusa JC, Levanon D, Wang Y, Franck MC, Kharchenko O, Adameyko I, Linnarsson S, Groner Y, Turner E, Ernfors P. Positional differences of axon growth rates between sensory neurons encoded by Runx3. EMBO Journal, 2012 Sep 12; 31(18):3718-29. *These authors contributed equally Papers not included in this thesis: Wang Y, Hadjab S, Lallemend F. A muscle-type specific function of RUNX3 for the construction of sensory-motor circuit. Manuscript. Petitpré C, Wu H, Sharma A, Tokarska A, Fontanet P, Wang Y, Helmbacher F, Yackle K, Silberberg G, Hadjab S, Lallemend F. Neuronal heterogeneity and stereotyped connectivity in the auditory afferent system. Nature Communications.2018 Sept 12; 9(1):3691. Wang Y*, Fisahn A*, Sinha I*, Nguyen DP, Sterzenbach U, Lallemend F, Hadjab S. Hippocampal transcriptome profile of persistent memory rescue in a mouse model of THRA1 mutation-mediated resistance to thyroid hormone. Scientific Reports, 2016 Jan 8; 6:18617. Vandenbosch R, Chocholova E, Robe PA, Wang Y, Lambert C, Moonen G, Lallemend F, Malgrange B, Hadjab S. A role for the canonical nuclear factorκB pathway in coupling neurotrophin-induced differential survival of developing spiral ganglion neurons. Frontiers in Cellular Neuroscience, 2013 Nov 28; 7:242.