Collapsin-1/Semaphorin-III/D Is Regulated Developmentally in Purkinje Cells and Collapses Pontocerebellar Mossy Fiber Neuronal Growth Cones

Abstract

Most axons in the CNS innervate specific subregions or layers of their target regions and form contacts with specific types of target neurons, but the molecular basis of this process is not well understood. To determine whether collapsin-1/semaphorin-III/D, a molecule known to repel specific axons, might guide afferent axons within their cerebellar targets, we characterized its expression by in situ hybridization and observed its effects on mossy and climbing fiber extension and growth cone size in vitro. In newborn mice sema-D is expressed by cerebellar Purkinje cells in parasagittal bands located medially and in some cells of the cerebellar nuclei. Later, sema-D expression in Purkinje cells broadens such that banded expression is no longer prominent, and expression is detected in progressively more lateral regions. By postnatal day 16, expression is observed throughout the cerebellar mediolateral axis. Collapsin-1 protein, the chick ortholog of sema-D, did not inhibit the extension of neurites from explants of inferior olivary nuclei, the source of climbing fibers that innervate Purkinje cells. In contrast, when it was applied to axons extending from basilar pontine explants, a source of mossy fiber afferents of granule cells, collapsin-1 caused most pontine growth cones to collapse, as evidenced by a reduction in growth cone size of up to 59%. Moreover, 63% of pontine growth cones arrested their extension or retracted. Its effects on mossy fiber extension and its distribution suggest that sema-D prevents mossy fibers from innervating inappropriate cerebellar target regions and cell types.

The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology

“…22,37 We interpret the punctate neuropil staining seen in the adults as reflecting the secretion of sema3A into the extracellular matrix. Given the sema3A cellular expression pattern, this seems most likely to be from the proximal dendrites of the Purkinje cells, though it might also arise from axons of neurons situated outside the cerebellar cortex (eg in the inferior olive).…”

“…24,57 This suggests that the local diffusion of sema3A may be acting as a chemorepellant for these synaptic contacts, and perhaps for others in the vicinity. 14,37 If there is causalty in the inverse correlation between sema3A and synaptic markers, one might predict similar alterations in other brain areas wherein synaptic proteins are decreased in schizophrenia, such as the hippocampal formation and dorsolateral prefrontal cortex. [1][2][3]58 A higher level of the semaphorin effector, collapsin response mediator protein 2, has been reported in the hippocampus in the disorder, 59 providing complementary evidence for an increased activity of the sema3A pathway.…”

The Stop Signal Revised: Immature Cerebellar Granule Neurons in the External Germinal Layer Arrest Pontine Mossy Fiber Growth

“…Zhang and Mason, unpublished observations), we never observed growth cone collapse and growth cone filopodia remained highly motile, suggesting that collapseinducing cues like semaphorins and Slits are not involved. Mem- bers of the FGF and Wnt families, released by mature granule cells or Purkinje cells, have also been implicated as regulators of mossy fiber differentiation (Rabacchi et al, 1999;Hall et al, 2000;Umemori et al, 2004). In the future, the analysis of (1) expression of specific ECM components in the cerebellum in the first postnatal week, (2) expression of heparin-binding inhibitory guidance morphogens, including FGFs and Wnts, and (3) interactions across these two groups of molecules should facilitate the identification of signals involved in mossy fiber growth regulation during axon extension and target selection.…”

Myelin‐, reactive glia‐, and scar‐derived CNS axon growth inhibitors: Expression, receptor signaling, and correlation with axon regeneration

“…There is constitutive expression of Sema 3A in meningeal fibroblast (Pasterkamp et al, 1998a(Pasterkamp et al, , 1998b(Pasterkamp et al, , 1999, mature cerebellar cells (Rabacchi et al, 1999), second-order olfactory bulb neurons (Pasterkamp et al, 1998c), and spinal motoneurons (Pasterkamp et al, 1998a(Pasterkamp et al, , 1998b(Pasterkamp et al, , 1999.…”