Motoneuronal Sema3C is essential for setting stereotyped motor tract positioning in limb-derived chemotropic semaphorins

Abstract

SUMMARYThe wiring of neuronal circuits requires complex mechanisms to guide axon subsets to their specific target with high precision. To overcome the limited number of guidance cues, modulation of axon responsiveness is crucial for specifying accurate trajectories. We report here a novel mechanism by which ligand/receptor co-expression in neurons modulates the integration of other guidance cues by the growth cone. Class 3 semaphorins (Sema3 semaphorins) are chemotropic guidance cues for various neuronal projections, among which are spinal motor axons navigating towards their peripheral target muscles. Intriguingly, Sema3 proteins are dynamically expressed, forming a code in motoneuron subpopulations, whereas their receptors, the neuropilins, are expressed in most of them. Targeted gain-and loss-of-function approaches in the chick neural tube were performed to enable selective manipulation of Sema3C expression in motoneurons. We show that motoneuronal Sema3C regulates the shared Sema3 neuropilin receptors Nrp1 and Nrp2 levels in opposite ways at the growth cone surface. This sets the respective responsiveness to exogenous Nrp1-and Nrp2-dependent Sema3A, Sema3F and Sema3C repellents. Moreover, in vivo analysis revealed a context where this modulation is essential. Motor axons innervating the forelimb muscles are exposed to combined expressions of semaphorins. We show first that the positioning of spinal nerves is highly stereotyped and second that it is compromised by alteration of motoneuronal Sema3C. Thus, the role of the motoneuronal Sema3 code could be to set population-specific axon sensitivity to limbderived chemotropic Sema3 proteins, therefore specifying stereotyped motor nerve trajectories in their target field.

The Nerve Growth Factor Receptor CD271 Is Crucial to Maintain Tumorigenicity and Stem-Like Properties of Melanoma Cells

“…We found, that CD271 knock-down abolished the capacity of melanoma cells to form heterogeneous tumors most likely due to down-regulation of mediators of melanoma invasion and metastasis ( GLI-2 [21], SOX2 [22] and ERBB3 [23]), angiogenesis ( IGFBP-2 [24]), proliferation ( FST [25] and MITF ) or chemoresistence ( RHOJ [26]). In addition, GSEA revealed that some of these genes are crucial for NCSC maintenance and migration, like SOX10 and SNAI2 or SEMA3C [27], respectively. We found SOX10 as one of the most down-regulated genes in CD271 k.d.…”

Expression patterns of Sema3A in developing amniote limbs: With reference to the diversification of peripheral nerve innervation

“…However, a recent study showed that the combined expression of class 3 semaphorins is present in the chick forelimb, and that Sema3C is involved in the pathfinding of spinal motor neurons (Sanyas et al . ). Thus, to confirm the role of class 3 semaphorins during amniote limb development, further expression analyses of Sema3C are necessary.…”

“…Among them, class 3 semaphorin family molecules, which act as a repulsive cue for developing axons, play important roles in the pathfinding of limb‐innervating neurons (Bonanomi & Pfaff ; Sanyas et al . ). In particular, knockout mice for Sema3A or its receptor (neuropilin1) exhibit incorrect innervation of spinal axons in the limb bud (Kitsukawa et al .…”

“…Previous studies have shown that attractive or repulsive guidance cues play a crucial role in axon guidance in both central and peripheral nervous systems in vertebrates (Cheng et al 1995;Tessier-Lavigne & Goodman 1996;Chisholm & Tessier-Lavigne 1999;Brose et al 1999;Tojima et al 2007). Among them, class 3 semaphorin family molecules, which act as a repulsive cue for developing axons, play important roles in the pathfinding of limb-innervating neurons (Bonanomi & Pfaff 2010;Sanyas et al 2012). In particular, knockout mice for Sema3A or its receptor (neuropilin1) exhibit incorrect innervation of spinal axons in the limb bud (Kitsukawa et al 1997;Taniguchi et al 1997).…”

Spinal Motor Neuron Migration and the Significance of Topographic Organization in the Nervous System

“…There is accumulating evidence that these families of proteins function in the specifi cation of motor axon trajectory in the limb (Huber et al 2005 ;Moret et al 2007 ;Huettl et al 2011 ;Sanyas et al 2012 ). Interestingly, since semaphoring-neuropilin signaling has been previously implicated in cortical neuron migration (Chen et al 2008 ), it would not be at all surprising if such signaling also impacts spinal motor neuron soma localisation, although so far no evidence of this function has been reported.…”