Neuropilin2 regulates the guidance of post-crossing spinal commissural axons in a subtype-specific manner

Neural Development

Zaven Kaprielian¹  Jane E Johnson⁴  Edward Martinez²  Ruihe Lin²  Edward Carlin³  Tracy S Tran² 

[1] Department of Pathology, Albert Einstein College of Medicine, Kennedy Center Room 624, 1410 Pelham Parkway South, Bronx, NY 10461, USA;Department of Biological Sciences, Rutgers University, Boyden 206, 195 University Ave., Newark, NJ 07102, USA;Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Kennedy Center Room 624, 1410 Pelham Parkway South, Bronx, NY 10461, USA;Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA

关键词: Spinal cord;    Development;    Neurog2;    Atoh1;    Semaphorins;   

Others  :  804426
DOI  :  10.1186/1749-8104-8-15

 received in 2013-04-19, accepted in 2013-07-19,  发布年份 2013

【 摘 要 】

Background

Spinal commissural axons represent a model system for deciphering the molecular logic that regulates the guidance of midline-crossing axons in the developing central nervous system (CNS). Whether the same or specific sets of guidance signals control the navigation of molecularly distinct subtypes of these axons remains an open and largely unexplored question. Although it is well established that post-crossing commissural axons alter their responsiveness to midline-associated guidance cues, our understanding of the repulsive mechanisms that drive the post-crossing segments of these axons away from the midline and whether the underlying guidance systems operate in a commissural axon subtype-specific manner, remains fragmentary at best.

Results

Here, we utilize axonally targeted transgenic reporter mice to visualize genetically distinct dorsal interneuron (dI)1 and dI4 commissural axons and show that the repulsive class 3 semaphorin (Sema3) guidance receptor Neuropilin 2 (Npn2), is selectively expressed on the dI1 population and is required for the guidance of post-crossing dI1, but not dI4, axons. Consistent with these observations, the midline-associated Npn2 ligands, Sema3F and Sema3B, promote the collapse of dI1, but not dI4, axon-associated growth cones in vitro. We also identify, for the first time, a discrete GABAergic population of ventral commissural neurons/axons in the embryonic mouse spinal cord that expresses Npn2, and show that Npn2 is required for the proper guidance of their post-crossing axons.

Conclusions

Together, our findings indicate that Npn2 is selectively expressed in distinct populations of commissural neurons in both the dorsal and ventral spinal cord, and suggest that Sema3-Npn2 signaling regulates the guidance of post-crossing commissural axons in a population-specific manner.

【 授权许可】

   
2013 Tran et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

【 参考文献 】

• [1]Bernhardt R, Chitnis A, Lindamer L, Kuwada J: Identification of spinal cord neurons in the embryonic and larval zebrafish. J Comp Neurol 1990, 302:607-616.
• [2]Silos-Santiago I, Snider WD: Development of commissural neurons in the embryonic rat spinal cord. J Comp Neurol 1992, 325:514-526.
• [3]Roberts A: Early functional organization of spinal neurons in developing lower vertebrates. Br Res Bull 2000, 53:585-593.
• [4]Stokke M, Nissen U, Glover J, Kiehn O: Projection patterns of commissural interneurons in the lumbar spinal cord of the neonatal rat. J Comp Neurol 2002, 447:349-359.
• [5]Helms A, Johnson J: Specification of dorsal spinal cord interneurons. Curr Opin Neurobiol 2003, 13:14-49.
• [6]Kadison SR, Kaprielian Z: Diversity of contralateral commissural projections in the embryonic rodent spinal cord. J Comp Neurol 2004, 472:411-422.
• [7]Helms AW, Johnson JE: Progenitors of dorsal commissural interneurons are defined by MATH1 expression. Development 1998, 125:919-928.
• [8]Gowan K, Helms AW, Hunsaker TL, Collisson T, Ebert PJ, Odom R, Johnson JE: Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 2001, 31:219-232.
• [9]Helms AW, Battiste J, Henke RM, Nakada Y, Simplicio N, Guillemot F, Johnson JE: Sequential roles for Mash1 and Ngn2 in the generation of dorsal spinal cord interneurons. Development 2005, 132:2709-2719.
• [10]Helms AW, Abney A, Ben-Arie N, Zoghbi H, Johnson JE: Autoregulation and multiple enhancers control Math1 expression in the developing nervous system. Development 2000, 127:1185-1196.
• [11]Lumpkin EA, Collisson T, Parab P, Omer-Abdalla A, Haeberle H, Chen P, Doetzlhofer A, White P, Groves A, Segil N, Johnson JE: Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr Patterns 2003, 3:389-395.
• [12]Simmons A, Horton S, Abney A, Johnson JE: Neurogenin2 expression in ventral and dorsal spinal neural tube progenitor cells is regulated by distinct enhancers. Dev Biol 2001, 229:327-329.
• [13]Henke RM, Savage TK, Meredith DM, Glasgow SM, Hori K, Dumas J, MacDonald RJ, Johnson JE: Neurog2 is a direct downstream target of the Ptf1a-Rbpj transcription complex in dorsal spinal cord. Development 2009, 136:2945-2954.
• [14]Nakada Y, Parab P, Simmons A, Omer-Abdalla A, Johnson JE: Separable enhancer sequences regulate the expression of the neural bHLH transcription factor neurogenin 1. Dev Biol 2004, 271:479-487.
• [15]Imondi R, Jevince A, Helms AW, Johnson JE, Kaprielian Z: Mis-expression of L1 on pre-crossing spinal commissural axons disrupts pathfinding at the ventral midline. Mol Cell Neurosci 2007, 36:462-471.
• [16]Reeber SL, Sakai N, Nakada Y, Dumas J, Dobrenis K, Johnson JE, Kaprielian Z: Manipulating Robo expression in vivo perturbs commissural axon pathfinding in the chick spinal cord. J Neurosci 2008, 28:8698-8708.
• [17]Phelps PE, Alijani A, Tran TS: Ventrally located commissural neurons express the GABAergic phenotype in the developing rat spinal cord. J Comp Neurol 1999, 409:285-298.
• [18]Tran TS, Alijani A, Phelps PE: Unique developmental patterns of GABAergic neurons in rat spinal cord. J Comp Neurol 2003, 456:112-126.
• [19]Dickson BJ, Gilestro GF: Regulation of commissural axon pathfinding by Slit and its Robo receptors. Annu Rev Cell Dev Biol 2006, 22:651-675.
• [20]Long H, Sabatier C, Ma L, Plump A, Yuan W, Ornitz DM, Tamada A, Murakami F, Goodman CS, Tessier-Lavigne M: Conserved roles for Slit and Robo proteins in midline commissural axon guidance. Neuron 2004, 42:213-223.
• [21]Chen Z, Gore BB, Long H, Ma L, Tessier-Lavigne M: Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion. Neuron 2008, 58:325-332.
• [22]Jaworski A, Long H, Tessier-Lavigne M: Collaborative and specializaed functions of Robo1 and Robo2 in spinal commissural axon guidance. J Neurosci 2010, 30:9445-9453.
• [23]Chen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M: Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 1997, 19:547-559.
• [24]Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD: Neuropilin is a semaphorin III receptor. Cell 1997, 90:753-762.
• [25]Yoshida Y: Semaphorin signaling in vertebrate neural circuit assembly. Front Mol Neurosci 2012, 5:71.
• [26]Zou Y, Stoeckli E, Chen H, Tessier-Lavigne M: Squeezing axons out of the gray matter: a role for Slit and Semaphorin proteins from midline and ventral spinal cord. Cell 2000, 102:363-375.
• [27]Nawabi H, Briancon-Marjollet A, Clark C, Sanyas I, Takamatsu H, Okuno T, Kumanogoh A, Bozon M, Takeshima K, Yoshida Y, Moret F, Abouzid K, Castellani V: A midline switch of receptor processing regulates commissural axon guidance in vertebrates. Genes & Devel 2010, 24:396-410.
• [28]Parra LM, Zou Y: Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing. Nat Neurosci 2010, 13:29-35.
• [29]Charoy C, Nawabi H, Reynaud F, Derrington E, Bozon M, Wright K, Falk J, Helmbacher F, Kindbeiter K, Castellani V: GDNF activates midline repulsion by Semaphorin3B via NCAM during commissural axon guidance. Neuron 2012, 75:1051-1066.
• [30]Caspary T, Anderson KV: Patterning cell types in the dorsal spinal cord: what the mouse mutants say. Nat Rev Neurosci 2003, 4:289-297.
• [31]Sakai N, Insolera R, Sillitoe RV, Shi SH, Kaprielian Z: Axon sorting within the spinal cord marginal zone via Robo-mediated inhibition of N-cadherin controls spinocerebellar tract formation. J Neurosci 2012, 32:15377-15387.
• [32]Kadison SR, Murakami F, Matise MP, Kaprielian Z: The role of floor plate contact in the elaboration of contralateral commissural projections within the embryonic mouse spinal cord. Dev Biol 2006, 296:499-513.
• [33]Augsburger A, Schuchardt A, Hoskins S, Dodd J, Butler S: BMPs as mediators of roof plate repulsion of commissural neurons. Neuron 1999, 24:127-141.
• [34]Imondi R, Wideman C, Kaprielian Z: Complementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: a possible role in constraining the orientation of longitudinally projecting axons. Development 2000, 127:1397-1410.
• [35]Kapfhammer JP, Xu H, Raper JA: The detection and quantification of growth cone collapsing activities. Nat Protoc 2007, 2:2005-2011.
• [36]Tran TS, Phelps PE: Axons crossing in the ventral commissure express L1 and GAD65 in the developing rat spinal cord. Dev Neurosci 2000, 22:228-236.
• [37]Tran TS, Cohen-Cory S, Phelps PE: Embryonic GABAergic spinal commissural neurons project rostrally to mesencephalic targets. J Comp Neurol 2004, 475:327-339.
• [38]Tamamaki N, Yanagawa Y, Tomioka R, Miyazaki J, Obata K, Kaneko T: Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol 2003, 467:60-79.
• [39]Tran TS, Rubio ME, Clem RL, Johnson D, Case L, Tessier-Lavigne M, Huganir RL, Ginty DD, Kolodkin AL: Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 2009, 462:1065-1069.
• [40]Beal JA, Bice TN: Neurogenesis of spinothalamic and spinocerebellar tract neurons in the lumbar spinal cord of the rat. Brain Res Dev Brain Res 1994, 78:49-56.
• [41]Plump AS, Erskine L, Sabatier C, Brose K, Epstein CJ, Goodman CS, Mason CA, Tessier-Lavigne M: Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Neuron 2002, 33:219-232.
• [42]Rabe N, Gezelius H, Vallstedt A, Memic F, Kullander K: Netrin-1-dependent spinal interneuron subtypes are required for the formation of left-right alternating locomotor circuitry. J Neurosci 2009, 29:15642-15649.
• [43]Lai HC, Klisch TJ, Roberts R, Zoghbi HY, Johnson JE: In vivo neuronal subtype-specific targets of Atoh1 (Math1) in dorsal spinal cord. J Neurosci 2011, 31:10859-10871.
• [44]Hernandez-Miranda LR, Cariboni A, Faux C, Ruhrberg C, Cho JH, Cloutier JF, Eickholt BJ, Parnavelas JG, Andrews WD: Robo1 regulates semaphorin signaling to guide the migration of cortical interneurons through the ventral forebrain. J Neurosci 2011, 31:6174-6187.
• [45]Stein E, Tessier-Lavigne M: Hierarchical organization of guidance receptors: silencing of Netrin attraction by Slit through a Robo/DCC receptor complex. Science 2001, 291:1928-1938.
• [46]Yaron A, Huang PH, Cheng HJ, Tessier-Lavigne M: Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins. Neuron 2005, 45:513-523.
• [47]Tran TS, Kolodkin AL, Bharadwaj R: Semaphorin regulation of cellular morphology. Annu Rev Cell Dev Biol 2007, 23:263-292.
• [48]Bonanomi D, Pfaff SL: Motor axon pathfinding. Cold Spring Harb Perspect Biol 2010, 2:a001735.
• [49]Kao TJ, Law C, Kania A: Eph and ephrin signaling: lessions learned from spinal motor neurons. Semin Cell Dev Biol 2012, 23:83-91.
• [50]Giger RJ, Cloutier JF, Sahay A, Prinjha RK, Levengood DV, Moore SE, Pickering S, Simmons D, Rastan S, Walsh FS, Kolodkin AL, Ginty DD, Geppert M: Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 2000, 25:29-41.
• [51]Jevince AR, Kadison SR, Pittman AJ, Chien CB, Kaprielian Z: Distribution of EphB receptors and ephrin-B1 in the developing vertebrate spinal cord. J Comp Neurol 2006, 497:734-750.
• [52]Bravo-Ambrosio A, Mastick G, Kaprielian Z: Motor axon exit from the mammalian spinal cord is controlled by the homeodomain protein Nkx2.9 via Robo-Slit signaling. Development 2012, 139:1435-1446.