Differential Requirement for Plexin-A3 and -A4 in Mediating Responses of Sensory and Sympathetic Neurons to Distinct Class 3 Semaphorins

Department of Biological Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
Neuron (Impact Factor: 15.05). 03/2005; 45(4):513-23. DOI: 10.1016/j.neuron.2005.01.013
Source: PubMed


The class 3 Semaphorins Sema3A and Sema3F are potent axonal repellents that cause repulsion by binding Neuropilin-1 and Neuropilin-2, respectively. Plexins are implicated as signaling coreceptors for the Neuropilins, but the identity of the Plexins that transduce Sema3A and Sema3F responses in vivo is uncertain. Here, we show that Plexin-A3 and -A4 are key determinants of these responses, through analysis of a Plexin-A3/Plexin-A4 double mutant mouse. Sensory and sympathetic neurons from the double mutant are insensitive to Sema3A and Sema3F in vitro, and defects in axonal projections in vivo correspond to those seen in Neuropilin-1 and -2 mutants. Interestingly, we found a differential requirement for these two Plexins: signaling via Neuropilin-1 is mediated principally by Plexin-A4, whereas signaling via Neuropilin-2 is mediated principally by Plexin-A3. Thus, Plexin-A3 and -A4 contribute to the specificity of axonal responses to class 3 Semaphorins.

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Available from: Hwai-Jong Cheng, Oct 09, 2015
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    • "For example, the axons of the branchiomotor neurons are controlled by both Sema3a/Npn1/plexinA4 and Sema3f/Npn2/plexinA3 complexes during facial nerve development, whereas visceromotor neuron axons are controlled by Sema3a/Npn1/plexinA4 complex only [22]. In another scenario, complexes of Sema3a, Npn1 and either plexinA3 or plexinA4 help to regulate axonal projections of sensory neurons in the dorsal root ganglia [23]. In contrast to plexinA3 and plexinA4, plexinA1 and plexinA2 typically transduce their signals through interactions with class 6 semaphorins in the nervous system [14], [24]–[27]. "
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    ABSTRACT: Statoacoustic ganglion (SAG) neurons project sensory afferents to appropriate targets in the inner ear to form functional vestibular and auditory circuits. Neuropilin1 (Npn1), a receptor for class 3 semaphorins, is required to generate appropriate afferent projections in SAG neurons; however, the ligands and coreceptors involved in Npn1 functioning remain unknown. Here we show that both plexinA1 and plexinA3 are expressed by SAG neurons, and plexinA1/plexinA3 double mutant mice show defects in afferent projections of SAG neurons in the inner ear. In control mice, sensory afferents of SAG neurons terminate at the vestibular sensory patches, whereas in plexinA1/plexinA3 double mutants, they extend more dorsally in the inner ear beyond normal vestibular target areas. Moreover, we find that semaphorin3a (Sema3a) is expressed in the dorsal otocyst, and Sema3a mutant mice show defects in afferent projections of SAG neurons similar to those observed in plexinA1/plexinA3 double mutants and in mice lacking a functional Npn1 receptor. Taken together, these genetic findings demonstrate that Sema3a repellent signaling plays a role in the establishment of proper afferent projections in SAG neurons, and this signaling likely occurs through a receptor complex involving Npn1 and either plexinA1 or plexinA3.
    PLoS ONE 08/2013; 8(8):e72512. DOI:10.1371/journal.pone.0072512 · 3.23 Impact Factor
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    • "Given that we find Npn2 expressed on both pre- and post-crossing segments of dI1 axons it is not clear why growth cones associated with post-crossing axons are selectively responsive to midline Semas, but the underlying mechanism could involve axon segment-specific receptor processing [27,29] or silencing [45]. It is well established that Npns form holoreceptor complexes with class A Plexins in order to mediate repulsion [25,46,47]. Accordingly, commissural axon-associated PlexinA1 [27] is a good candidate for facilitating the response of post-crossing dI1 growth cones to Sema3B/3F and this possibility can be addressed by analyzing the consequences of inactivating Plexin A1 in Atoh1-tauGFP reporter mice. "
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    ABSTRACT: 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. 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. 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.
    Neural Development 07/2013; 8(1):15. DOI:10.1186/1749-8104-8-15 · 3.45 Impact Factor
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    • "Whole-Mount Staining E12.5 mouse embryos (Kif2a KO and WT littermates) were stained as described (Yaron et al., 2005). "
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    ABSTRACT: Extensive axonal pruning and neuronal cell death are critical events for the development of the nervous system. Like neuronal cell death, axonal elimination occurs in discrete steps; however, the regulators of these processes remain mostly elusive. Here, we identify the kinesin superfamily protein 2A (KIF2A) as a key executor of microtubule disassembly and axonal breakdown during axonal pruning. Knockdown of Kif2a, but not other microtubule depolymerization or severing proteins, protects axonal microtubules from disassembly upon trophic deprivation. We further confirmed and extended this result to demonstrate that the entire degeneration process is delayed in neurons from the Kif2a knockout mice. Finally, we show that the Kif2a-null mice exhibit normal sensory axon patterning early during development, but abnormal target hyperinnervation later on, as they compete for limited skin-derived trophic support. Overall, these findings reveal a central regulatory mechanism of axonal pruning during development.
    Cell Reports 04/2013; 3(4). DOI:10.1016/j.celrep.2013.03.005 · 8.36 Impact Factor
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