ReviewDevelopment of precerebellar nuclei: instructive factors and intracellular mediators in neuronal migration, survival and axon pathfinding
Introduction
A basic property of immature neurons in the developing nervous system is their ability to migrate from their birthplace in proliferative zones of the developing brain to their final location in the adult brain. The precerebellar system, located in the hindbrain, provides the principal input to the cerebellum and is essential for coordinated motor activity. Precerebellar young postmitotic neurons undergo subsequent long distance tangential circumferential migration from the germinal neuroepithelium (rhombic lip; Fig. 1A) to their final position in the adult hindbrain. Neurons emit a leading process and each cell nucleus of the migrating cell moves within its own leading process through a neurophilic migration, i.e. nucleokinesis (Fig. 1B). Derivatives from rostral and caudal rhombic lips are quite diverse. The dorsalmost region of the rostral hindbrain differentiates not solely as cerebellar granule neurons but also gives rise to isthmic neurons [64], [100] and to other rostral hindbrain neurons, including the locus coeruleus, the reticularis pontis and basal pontine gray (PN) nuclei [5], [57]. The different populations of precerebellar neurons (PCN) that are derivatives from the caudal rhombic lip include, among others, external cuneatus (EC), lateral reticular (LR) and inferior olivary (IO) nuclei. In the present review, we will focus on these PCN since most molecular data have been recently reported for PCN from the caudal rhombic lip. PCN present overlapping proliferation periods from the upper to the lower rhombic lip [93]. Nevertheless, they show quite distinct tangential migratory pathways and final localizations and their intrinsic characteristics have been anatomically well-documented [4], [15], [40]. Thus, PCN provide an appropriate comparative model to study decisions that govern the neuronal specification. The migration of ION occurs through the submarginal stream [3], [4], [13], [14] whereas other PCN migrate through the marginal stream (Figs. 1C–D). Axons of all PCN first cross the floor-plate–a ventro-medial glial structure that extends all along the antero-posterior axis of the CNS–and then reach their cerebellar entry whereas their somata do not respond to signals secreted by the floor-plate in the same way: the cell bodies of LRN/ECN cross the floor-plate and continue their translocation until they reach their final location in the contralateral hindbrain contrary to ION cell bodies that stop before crossing the floor-plate although their axons have already crossed the latter (Figs. 1C–D).
These observations suggest that the floor-plate, an intermediate target for those migrating neurons, or the cerebellum, the ultimate target, contain or release signals that affect olivary neurons differently from other PCN (Fig. 1D). Mechanisms of nuclear translocation are likely to be different, at least partially, from those that govern the pathfinding of the leading process itself since there is no absolute coupling between both phenomena, at least for ION. The analysis of Rho-GTPases involved in PCN migration in vivo and in vitro has underlined that axon outgrowth and nuclear migration were not strictly dependent events since axon outgrowth could occur when nucleokinesis was blocked whereas nuclear migration could occur when axon elongation was affected [21].
Section snippets
Cues directing migration and survival of PCN neurons
Both alar- and roof-plates were proposed as a source of molecular cues that could direct PCN migrations. Taniguchi et al. [95] have reported that LRN/ECN lose their attractive response to the floor-plate upon reaching it. Subsequently, they acquire responsiveness to alar-plate-derived attractive cues that could allow the correct positioning of various PCN cell bodies in the hindbrain, ipsi- or contralaterally to their site of birth. Nevertheless, the underlying molecular mechanisms still remain
Intracellular mediators involved in neurophilic migration of PCN: remodeling the microtubule and actin cytoskeletons
The signaling cascades governing neuronal migration and axonal guidance link extracellular signals to actin and microtubules cytoskeletal components. Extracellular cues must be in particular relayed to the actin cytoskeleton, a dynamic network of filaments and associated proteins that is largely responsible for cell motility [51] as well as to microtubule-associated proteins. Members of the Rho subfamily of small GTPases may play pivotal roles in conveying signals to the cytoskeleton [39], [92]
Concluding remarks
Cell bodies move through a series of jumps, as reported in various neuronal systems [21], [37], [73]. Recent in vitro data have reported that (i) axon outgrowth and migration of PCN are not strictly dependent processes since a shortened axon extension allows nuclear translocation, and axon outgrowth can develop without nucleokinesis; (ii) Rac1/Cdc42 are necessary for axon growth of PCN while RhoA/B/C are necessary for nuclear migration, axon fasciculation and tropism in response to netrin-1. In
Acknowledgments
Special thanks to Cuca Alvarado-Mallart–to whom this review is dedicated–a rigorous and enthusiastic scientist, as well as a generous and open-minded woman.
Great thanks to Constantino Sotelo for making me discover the fascinating field of neuronal migrations in the precerebellar system and for the stimulating discussions we had at the beginning of this scientific adventure.
We also thank Dr. Isabelle Le Roux for the critical reading of the manuscript and Annie Goldman for proof-reading in
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