Cas Adaptor Proteins Coordinate Sensory Axon Fasciculation

Abstract

Development of complex neural circuits like the peripheral somatosensory system requires intricate mechanisms to ensure axons make proper connections. While much is known about ligand-receptor pairs required for dorsal root ganglion (DRG) axon guidance, very little is known about the cytoplasmic effectors that mediate cellular responses triggered by these guidance cues. Here we show that members of the Cas family of cytoplasmic signaling adaptors are highly phosphorylated in central projections of the DRG as they enter the spinal cord. Furthermore, we provide genetic evidence that Cas proteins regulate fasciculation of DRG sensory projections. These data establish an evolutionarily conserved requirement for Cas adaptor proteins during peripheral nervous system axon pathfinding. They also provide insight into the interplay between axonal fasciculation and adhesion to the substrate.

An adhesion signaling axis involving Dystroglycan, β1-Integrin and Cas adaptor proteins regulates the establishment of the cortical glial scaffold

“…As mentioned above, three Cas paralogs are expressed during vertebrate development: p130Cas/BCar1, CasL/Nedd9 and Sin/Efs (Merrill et al, 2004;Huang et al, 2007;Liu et al, 2007;Riccomagno et al, 2014;Vahedi-Hunter et al, 2018). A fourth family member, Cass4, initially believed to be a pseudogene, appears to only be expressed in the adult (Merrill et al, 2004;Deneka et al, 2015).…”

“…The highly overlapping expression and redundant roles played by Cas proteins make using the Cas TcKO mice of vital importance to understand Cas function (Fig 1A; Supplemental Fig. 1A-B) (Riccomagno et al, 2014;Vahedi-Hunter et al, 2018). To drive Cre recombinase expression we used the Emx1Cre line, which expresses Cre in early cortical neural progenitors and radial glial cells (RGCs) in the forebrain (Gorski et al, 2002), resulting in recombination in RGCs themselves and the excitatory neurons in the cortex and hippocampus (Supplemental Fig.…”

“…As mentioned above, three Cas paralogs are expressed during vertebrate development: p130Cas/BCar1 , CasL/Nedd9 and Sin/Efs [58,59,60,61,62]. A fourth family member, Cass4 , initially believed to be a pseudogene, appears to only be expressed in the adult [58,64].…”

“…Cas family members have been shown to mediate a variety of biological processes including cell migration and changes in cell morphology in vitro (Burnham et al, 1996;Klemke et al, 1998;Cho & Klemke, 2000;Tikhmyanova et al, 2010). Three of the four mammalian Cas genes are expressed in the developing rodent CNS, including the dorsal telencephalon (Merrill et al, 2004;Huang et al, 2007;Liu et al, 2007;Riccomagno et al, 2014;Vahedi-Hunter et al, 2018). Using a conditional gene targeting approach in the mouse to inactivate these three Cas genes, we previously uncovered a cell-autonomous role for Cas adaptor proteins acting redundantly to mediate integrin signaling during the organization of the retinal ganglion cell layer (GCL) (Riccomagno et al, 2014).…”

“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. Riccomagno et al, 2014;Vahedi-Hunter et al, 2018). Using a conditional gene targeting approach in the mouse to inactivate these three Cas genes, we previously uncovered a cell-autonomous role for Cas adaptor proteins acting redundantly to mediate integrin signaling during the organization of the retinal ganglion cell layer (GCL) (Riccomagno et al, 2014).…”