JAKMIP1: Translating the Message for Social Behavior
Authors: Jay Penney, Li-Huei Tsai
Journal: Neuron (2015)

In this issue of Neuron, Berg et al., 2015Berg J.M. Lee C. Chen L. Galvan L. Cepeda C. Chen J.Y. Peñagarikano O. Stein J.L. Li A. Oguro-Ando A. et al.Neuron. 2015; 88 (this issue): 1173-1191Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar uncover multifaceted roles for janus kinase and microtubule-interacting protein 1 (JAKMIP1) in regulating neuronal mRNA translation and establish JAKMIP1 knockout mice as an important model to study autism spectrum disorder-associated phenotypes. In this issue of Neuron, Berg et al., 2015Berg J.M. Lee C. Chen L. Galvan L. Cepeda C. Chen J.Y. Peñagarikano O. Stein J.L. Li A. Oguro-Ando A. et al.Neuron. 2015; 88 (this issue): 1173-1191Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar uncover multifaceted roles for janus kinase and microtubule-interacting protein 1 (JAKMIP1) in regulating neuronal mRNA translation and establish JAKMIP1 knockout mice as an important model to study autism spectrum disorder-associated phenotypes. Synaptic plasticity is a fundamental process that allows for the strengthening or weakening of communication between neurons in the brain (Malenka and Bear, 2004Malenka R.C. Bear M.F. Neuron. 2004; 44: 5-21Abstract Full Text Full Text PDF PubMed Scopus (2936) Google Scholar). Synaptic plasticity can underlie circuit-based changes in behavior and is critical for learning, memory, and a myriad of other brain functions. Numerous cellular processes, including modification of existing proteins as well as transcription and translation of new proteins, coordinate to elicit plasticity-based changes in neuronal function. Perturbation of any of these processes can disrupt plasticity mechanisms and result in neurological disease. ASDs are a common and heterogeneous group of neurological disorders defined by deficits in three core areas: social interaction, communication, as well as restrictive and repetitive behaviors (Kelleher and Bear, 2008Kelleher 3rd, R.J. Bear M.F. Cell. 2008; 135: 401-406Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar). A number of single gene mutations and recurrent chromosomal aberrations result in syndromes that exhibit ASD phenotypes. A large portion of ASD cases also result from de novo mutations affecting one of hundreds of different genes that can lead to autism spectrum phenotypes (Krumm et al., 2014Krumm N. O'Roak B.J. Shendure J. Eichler E.E. Trends Neurosci. 2014; 37: 95-105Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). Thus, identifying common pathways and convergent pathophysiological mechanisms provides a powerful approach to understanding the complex genetic landscape of ASDs. Mutations affecting synaptic proteins and regulators of embryonic brain development are major contributors to ASD cases (Chang et al., 2015Chang J. Gilman S.R. Chiang A.H. Sanders S.J. Vitkup D. Nat. Neurosci. 2015; 18: 191-198Crossref PubMed Scopus (135) Google Scholar). Dysregulation of neuronal protein synthesis can also lead to ASD phenotypes (Kelleher and Bear, 2008Kelleher 3rd, R.J. Bear M.F. Cell. 2008; 135: 401-406Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar). Localized mRNA translation at postsynaptic sites is controlled by neuronal activity and is critical for various forms of synaptic plasticity. Proper regulation of synaptic protein synthesis requires transport of specific mRNAs to synaptic sites and the regulation of their local translation in response to the appropriate stimuli. The translational repressor fragile X mental retardation protein (FMRP) is one important regulator of both mRNA transport and local translation in neurons (Ebert and Greenberg, 2013Ebert D.H. Greenberg M.E. Nature. 2013; 493: 327-337Crossref PubMed Scopus (418) Google Scholar). FMRP silencing leads to fragile X syndrome, a disorder characterized by intellectual disability and often ASD phenotypes. Similarly, overactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, a major regulator of both global and synaptic protein synthesis, is associated with syndromic forms of ASD (Kelleher and Bear, 2008Kelleher 3rd, R.J. Bear M.F. Cell. 2008; 135: 401-406Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar). In an effort to identify convergent molecular mechanisms in ASD, the Geschwind group previously identified JAKMIP1 as differentially expressed in ASD patients and in two mouse models of ASD: Fmr1 KO and 15q11-q13 duplication mice (Nishimura et al., 2007Nishimura Y. Martin C.L. Vazquez-Lopez A. Spence S.J. Alvarez-Retuerto A.I. Sigman M. Steindler C. Pellegrini S. Schanen N.C. Warren S.T. Geschwind D.H. Hum. Mol. Genet. 2007; 16: 1682-1698Crossref PubMed Scopus (227) Google Scholar). Here, the authors present an impressive multidisciplinary analysis of JAKMIP1 function in the mammalian brain. Berg et al., 2015Berg J.M. Lee C. Chen L. Galvan L. Cepeda C. Chen J.Y. Peñagarikano O. Stein J.L. Li A. Oguro-Ando A. et al.Neuron. 2015; 88 (this issue): 1173-1191Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar generate and characterize a JAKMIP1 KO mouse, as well as identifying JAKMIP1 binding partners in the developing brain. This work identified numerous protein synthesis-related binding partners and revealed multiple molecular, cellular, electrophysiological, and behavioral abnormalities following loss of JAKMIP1. The findings clearly establish JAKMIP1 as an important regulator of neuronal translation whose disruption results in ASD-associated phenotypes. Berg et al. begin by utilizing Multidimensional Protein Identification Technology (MudPIT) to examine the JAKMIP1 interactome in the early postnatal mouse brain. This critical period of synaptogenesis coincides with the peak period of JAKMIP1 protein expression. They identified a core set of 33 interacting proteins, a third of which were protein synthesis regulators. Intriguingly, numerous JAKMIP1 binding proteins were also components of messenger ribonucleoprotein (mRNP) granules and known interactors of FMRP. As FMRP mRNP granules are important for mRNA transport to synaptic sites, and for regulating the interaction between specific mRNAs and the translation machinery, these observations suggest that JAKMIP1 could also be involved in both of these processes. Next, the authors validated a subset of the JAKMIP1 interactions by co-immunoprecipitation (co-IP) and examined the ribosome association of JAKMIP1 and some of its interacting proteins. Polysome fractionation experiments demonstrated that JAKMIP1 associates with mRNP granules and actively translating ribosomes (Figure 1). Furthermore, two JAKMIP1-binding proteins, PABPC1 and DDX5, were depleted from actively translating ribosomes in brain tissue from JAKMIP1 KO mice, suggesting ribosome function could be altered. To directly examine whether JAKMIP1 affects neuronal protein synthesis, the authors then used the FUNCAT (fluorescent non-canonical amino acid tagging) technique to fluorescently label newly synthesized proteins in cultured neural progenitor cells. These experiments revealed reductions in new protein synthesis in both the soma and neurites of cells lacking JAKMIP1, with a qualitatively stronger effect in neurites. These findings suggest that loss of JAKMIP1 alters global protein synthesis in neuronal cells, in addition to likely affecting synapse-localized translation. Having established that JAKMIP1 binds to multiple FMRP-interacting proteins and regulates neuronal translation, the authors next focused on examining possible links between JAKMIP1 and FMRP. While FMRP was not identified in the MudPIT screen for JAKIMP1 interactors, the authors could co-IP JAKMIP1 with FMRP and vice versa using less stringent conditions. Previous findings showed that JAKMIP1 associated with neuronal granules, was mobile in dendrites, and could bind mRNA (Couve et al., 2004Couve A. Restituito S. Brandon J.M. Charles K.J. Bawagan H. Freeman K.B. Pangalos M.N. Calver A.R. Moss S.J. J. Biol. Chem. 2004; 279: 13934-13943Crossref PubMed Scopus (48) Google Scholar, Vidal et al., 2009Vidal R.L. Valenzuela J.I. Luján R. Couve A. BMC Neurosci. 2009; 10: 37Crossref PubMed Scopus (9) Google Scholar). These observations prompted the authors to examine whether JAKMIP1 could bind to a similar subset of neuronal mRNAs as are bound by FMRP. Using RNA immunoprecipitation (RIP) experiments from postnatal cortical and striatial tissue, the authors found that indeed JAKMIP1 bound many of the same mRNAs that are known to bind FMRP. They also found that protein levels corresponding to a subset of the bound mRNAs (PSD-95 in the cortex and GluN2A, GluN2B, and Shank2 in striatial synaptosomes) were reduced in juvenile JAKMIP1 KO mice with no change in total mRNA levels. Furthermore, polysome bound PSD-95 mRNA was reduced by loss of JAKMIP1, consistent with the idea that JAKMIP1 normally promotes translation of the mRNAs it binds. Interestingly, while JAKMIP1 and FMRP bound many of the same neuronal mRNAs, neither FMRP binding nor JAKMIP1 binding to the same set of target mRNAs was significantly affected in the absence of the other protein. As such, further study will be required to elucidate the nature and importance of the JAKMIP1-FMRP interaction. At minimum it appears that JAKMIP1 and FMRP interact with a number of common targets, perhaps via parallel mechanisms. Further study will also be required to determine the complete set of mRNAs bound by JAKMIP1, as well as the importance of JAKMIP1 for their transport and/or translation. Berg et al., 2015Berg J.M. Lee C. Chen L. Galvan L. Cepeda C. Chen J.Y. Peñagarikano O. Stein J.L. Li A. Oguro-Ando A. et al.Neuron. 2015; 88 (this issue): 1173-1191Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar next examined the effects of JAKMIP1 loss on cognitive function and behavior. As mouse models of numerous different protein synthesis regulators exhibit ASD-related phenotypes (Kelleher and Bear, 2008Kelleher 3rd, R.J. Bear M.F. Cell. 2008; 135: 401-406Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar), the authors hypothesized that mice lacking JAKMIP1 might also show such phenotypes. Indeed, JAKMIP1 KO mice displayed social interaction defects, excessive grooming, increased perseverance, and altered postnatal ultrasonic vocalizations. Each of these phenotypes is commonly found in ASD mouse models and is thought to correlate with the alterations in sociability, communication, and restrictive behavior observed in ASD patients (Pasciuto et al., 2015Pasciuto E. Borrie S.C. Kanellopoulos A.K. Santos A.R. Cappuyns E. D'Andrea L. Pacini L. Bagni C. Neurobiol. Learn. Mem. 2015; 124: 71-87Crossref PubMed Scopus (57) Google Scholar). In addition to ASD related behaviors, these mice also exhibited deficits in cued fear conditioning, motor learning, and anxiety/impulsivity. Thus, loss of JAKMIP1 results in multiple behavioral abnormalities, including ASD-like behaviors. These findings also suggest that the altered JAKMIP1 levels found in ASD patients and mouse models likely contribute to their behavioral phenotypes. The various molecular and behavioral alterations found in JAKMIP1 KO mice suggest that neuronal function might also be affected in these animals. Defects in cortical circuitry and function are well documented in ASD cases and models; however, defects in striatial transmission and corticostriatal connectivity also contribute to ASD-related phenotypes (Chang et al., 2015Chang J. Gilman S.R. Chiang A.H. Sanders S.J. Vitkup D. Nat. Neurosci. 2015; 18: 191-198Crossref PubMed Scopus (135) Google Scholar). Thus, the authors examined evoked AMPA- and NMDA-mediated currents in postnatal striatial medium spiny neurons (MSNs), finding increased charge transfer through both types of receptors. Interestingly, 25% of MSNs from JAKMIP1 KO mice failed to exhibit NMDA currents, a phenotype not observed in wild-type mice. The authors did not report any change in striatial AMPA receptor expression; however, the altered synaptic GluN2A and GluN2B expression they observed presumably contributes to the NMDA receptor current defects found in JAKMIP1 KO mice. Of note, while both GluN2A and GluN2B levels were reduced, the authors observed a qualitatively greater reduction in GluN2B, likely altering GluN2B/GluN2A stoichiometry. This alteration in NMDA receptor subunit composition, together with the lack of any NMDA currents in a subset of MSNs, suggests that JAKMIP1 KO mice may exhibit delayed MSN maturation. Consistently, in adult JAKMIP1 KO mice, striatial GluN2A and GluN2B levels, as well as AMPA and NMDA receptor currents, were no longer different from wild-type controls. The normalization of synaptic protein and electrophysiological defects in adult JAKMIP1 KO mice suggests the possibility that additional mechanisms could underlie the observed alterations in adult behavior. Indeed, Berg et al., 2015Berg J.M. Lee C. Chen L. Galvan L. Cepeda C. Chen J.Y. Peñagarikano O. Stein J.L. Li A. Oguro-Ando A. et al.Neuron. 2015; 88 (this issue): 1173-1191Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar report a microcephaly phenotype in JAKMIP1 KO mice, while a previous study observed altered neocortical neuronal migration following knockdown of JAKMIP1 in utero (Vidal et al., 2012Vidal R.L. Fuentes P. Valenzuela J.I. Alvarado-Diaz C.P. Ramirez O.A. Kukuljan M. Couve A. Mol Cell Neurosci. 2012; 51: 1-11Crossref PubMed Scopus (5) Google Scholar), suggesting roles for JAKMIP1 in neurodevelopmental processes. Earlier studies also reported that JAKMIP1 could bind to GABA receptor mRNA and protein, indicating that GABA receptor signaling could be altered in these mice (Couve et al., 2004Couve A. Restituito S. Brandon J.M. Charles K.J. Bawagan H. Freeman K.B. Pangalos M.N. Calver A.R. Moss S.J. J. Biol. Chem. 2004; 279: 13934-13943Crossref PubMed Scopus (48) Google Scholar, Vidal et al., 2009Vidal R.L. Valenzuela J.I. Luján R. Couve A. BMC Neurosci. 2009; 10: 37Crossref PubMed Scopus (9) Google Scholar). As such, future efforts will be required to fully understand the basis of the behavioral defects arising from loss of JAKMIP1. Similarly, the exact role(s) of JAKMIP1 in regulating neuronal translation remain unclear. The association of JAKMIP1 with mRNP particles and mRNAs, together with earlier reports indicating that JAKMIP1 associates with the microtubule motor protein kinesin-1 and is mobile in dendrites (Vidal et al., 2007Vidal R.L. Ramirez O.A. Sandoval L. Koenig-Robert R. Hartel S. Couve A. Mol Cell Neurosci. 2007; 35: 501-512Crossref PubMed Scopus (27) Google Scholar, Vidal et al., 2012Vidal R.L. Fuentes P. Valenzuela J.I. Alvarado-Diaz C.P. Ramirez O.A. Kukuljan M. Couve A. Mol Cell Neurosci. 2012; 51: 1-11Crossref PubMed Scopus (5) Google Scholar), suggest that JAKMIP1 is involved in mRNA transport to synaptic sites; however, this possibility has not yet been formally tested. Likewise, the ribosomal association of JAKMIP1, reduced protein synthesis observed in JAKMIP1 KO neurons, and reduced polysome association of PABPC1 and DDX5 suggest possible defects in ribosome function. Thus, whether a general defect in cellular protein synthesis or a more specific effect on local synaptic translation is responsible for the cellular and behavioral phenotypes of JAKMIP1 KO mice remains an open question. While further efforts will be necessary to fully understand the details of JAKMIP1 function, Berg et al., 2015Berg J.M. Lee C. Chen L. Galvan L. Cepeda C. Chen J.Y. Peñagarikano O. Stein J.L. Li A. Oguro-Ando A. et al.Neuron. 2015; 88 (this issue): 1173-1191Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar have made a major contribution to our understanding of JAKMIP1 biology, establishing this protein as a critical regulator of mRNA translation in the mammalian brain (Figure 1). Furthermore, the authors have uncovered numerous molecular, cellular, and electrophysiological defects in JAKMIP1 KO mice leading to ASD-related phenotypes. This novel ASD model reinforces the role of neuronal translation in ASD etiology and provides a platform for further study of these processes. JAKMIP1 likely also serves as a convergence point for a subset of molecules or pathways relevant to ASD, as well as itself regulating multiple processes important for neuronal function. JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in MouseBerg et al.NeuronNovember 25, 2015In BriefBerg et al. demonstrate a novel role for JAKMIP1 in regulating mRNA translation during neural development. JAKMIP1 knockout reduces translation of several PSD proteins, disrupts glutamatergic signaling, and causes ASD-related behaviors, consistent with an important role in modulating neuronal function. Full-Text PDF Open Archive