The nervous system requires metabolites and oxygen supplied by the neurovascular network, but this necessitates close apposition of neurons and endothelial cells. We find motor neurons attract ...vessels with long-range VEGF signaling, but endothelial cells in the axonal pathway are an obstacle for establishing connections with muscles. It is unclear how this paradoxical interference from heterotypic neurovascular contacts is averted. Through a mouse mutagenesis screen, we show that Plexin-D1 receptor is required in endothelial cells for development of neuromuscular connectivity. Motor neurons release Sema3C to elicit short-range repulsion via Plexin-D1, thus displacing endothelial cells that obstruct axon growth. When this signaling pathway is disrupted, epaxial motor neurons are blocked from reaching their muscle targets and concomitantly vascular patterning in the spinal cord is altered. Thus, an integrative system of opposing push-pull cues ensures detrimental axon-endothelial encounters are avoided while enabling vascularization within the nervous system and along peripheral nerves.
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•Plexin-D1 is required in ECs to establish axial MN connectivity•MNs release attractive and repulsive signals that pattern blood vessels•Motor axons displace endothelial obstacles with Sema3C/Plexin-D1 signaling•Neurovascular crosstalk links axon targeting of neuronal subtypes to vascularization
Axons navigate complex environments where unwanted encounters with other cells might hinder their course. Martins et al. identify a selective obstacle-removal pathway based on short-range Sema3C/Plexin-D1 repulsive signaling that motor neurons employ to evade collisions with blood vessels while enabling assembly of interdependent neurovascular networks through attraction of endothelial cells.
Cajal–Retzius (CR) cells play a crucial role in the formation of the cerebral cortex, yet the molecules that control their development are largely unknown. Here, we show that Ebf transcription ...factors are expressed in forebrain signalling centres—the septum, cortical hem and the pallial–subpallial boundary—known to generate CR cells. We identified Ebf2, through fate mapping studies, as a novel marker for cortical hem- and septum-derived CR cells. Loss of Ebf2 in vivo causes a transient decrease in CR cell numbers on the cortical surface due to a migratory defect in the cortical hem, and is accompanied by upregulation of Ebf3 in this and other forebrain territories that produce CR cells, without affecting proper cortical lamination. Accordingly, using in vitro preparations, we demonstrated that both Ebf2 and Ebf3, singly or together, control the migration of CR cells arising in the cortical hem. These findings provide evidence that Ebfs directly regulate CR cell development.
► Ebf2 is a novel marker for hem- and septum-derived Cajal–Retzius cells. ► Ebf2 mutant shows a transient migratory defect of hem-derived Cajal–Retzius cells. ► Ebf3 is expressed in similar territories as Ebf2 and rescues Ebf2 mutant phenotype. ► Both Ebf2 and Ebf3 are required for Cajal–Retzius cell migration.
The collier/Olf1/EBF family genes encode helix-loop-helix transcription factors (TFs) highly conserved in evolution, initially characterized for their roles in the immune system and in various ...aspects of neural development. The
Early B cell Factor 2
(
Ebf2
) gene plays an important role in the establishment of cerebellar cortical topography and in Purkinje cell (PC) subtype specification. In the adult cerebellum,
Ebf2
is expressed in zebrin II (ZII)-negative PCs, where it suppresses the ZII+ molecular phenotype. However, it is not clear whether
Ebf2
is restricted to a PC subset from the onset of its expression or is initially distributed in all PCs and silenced only later in the prospective ZII+ subtype. Moreover, the dynamic distribution and role of
Ebf2
in the differentiation of other cerebellar cells remain unclarified. In this paper, by genetic fate mapping, we determine that
Ebf2
mRNA is initially found in all PC progenitors, suggesting that unidentified upstream factors silence its expression before completion of embryogenesis. Moreover we show
Ebf2
activation in an early born subset of granule cell (GC) precursors homing in the anterior lobe. Conversely,
Ebf2
transcription is repressed in other cerebellar cortex interneurons. Last, we show that, although
Ebf2
only labels the medial cerebellar nuclei (CN) in the adult cerebellum, the gene is expressed prenatally in projection neurons of all CN. Importantly, in
Ebf2
nulls, fastigial nuclei are severely hypocellular, mirroring the defective development of anterior lobe PCs. Our findings further clarify the roles of this terminal selector gene in cerebellar development.
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