CRMP4 suppresses apical dendrite bifurcation of CA1 pyramidal neurons in the mouse hippocampus

Abstract

Collapsin response mediator proteins (CRMPs) are a family of cytosolic phosphoproteins that consist of 5 members (CRMP 1-5). CRMP2 and CRMP4 regulate neurite outgrowth by binding to tubulin heterodimers, resulting in the assembly of microtubules. CRMP2 also mediates the growth cone collapse response to the repulsive guidance molecule semaphorin-3A (Sema3A). However, the role of CRMP4 in Sema3A signaling and its function in the developing mouse brain remain unclear. We generated CRMP4À/À mice in order to study the in vivo function of CRMP4 and identified a phenotype of proximal bifurcation of apical dendrites in the CA1 pyramidal neurons of CRMP4À/À mice. We also observed increased dendritic branching in cultured CRMP4À/À hippocampal neurons as well as in cultured cortical neurons treated with CRMP4 shRNA. Sema3A induces extension and branching of the dendrites of hippocampal neurons; however, these inductions were compromised in the CRMP4À/À hippocampal neurons. These results suggest that CRMP4 suppresses apical dendrite bifurcation of CA1 pyramidal neurons in the mouse hippocampus and that this is partly dependent on Sema3A signaling.

Collapsin Response Mediator Protein 4 Regulates Growth Cone Dynamics through the Actin and Microtubule Cytoskeleton

“…1C and Ref. 29). CRMP4 proteins levels were undetectable in CRMP4Ϫ/Ϫ mice by Western blotting or immunofluorescent staining with an anti-CRMP4 antibody (Fig.…”

“…However, the uniform distribution of CRMP4 throughout axon and dendritic processes in hippocampal neurons differs from that of CRMP2, which is enriched in the distal parts of growing axons and growth cones (42). The distribution of CRMP4 suggests additional roles in dendritic formation, and indeed, hippocampal neurons from CRMP4Ϫ/Ϫ mice exhibit enhanced dendritic branching in culture with no change in total dendritic length (29). In vivo, CA1 pyramidal neurons from CRMP4Ϫ/Ϫ mice exhibit a proximal bifurcation of their apical dendrites perhaps in part as a result of desensitization to Semaphorin3A signaling (29).…”

“…The distribution of CRMP4 suggests additional roles in dendritic formation, and indeed, hippocampal neurons from CRMP4Ϫ/Ϫ mice exhibit enhanced dendritic branching in culture with no change in total dendritic length (29). In vivo, CA1 pyramidal neurons from CRMP4Ϫ/Ϫ mice exhibit a proximal bifurcation of their apical dendrites perhaps in part as a result of desensitization to Semaphorin3A signaling (29). The mild phenotype in the hippocampus of the CRMP4 Ϫ/Ϫ mice suggests that there is functional compensation that promotes hippocampal neurite outgrowth perhaps by other CRMP family members (29).…”

Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling

“…[43][44][45] The lowered affinity of phosphorylated CRMPs to tubulin may be responsible for Sema3A-induced axon repulsion or growth cone collapse. 36,45,46 As substrates, CRMPs also physically interact with the intracellular molecule interacting with CasL (MICAL), and transduce Sema3A signaling. 47,48 Another possible mechanism for Sema3A-induced cytoskeletal reorganization is the regulation of the function of 42 PlexinA GAP activity is regulated by FERM, RhoGEF and pleckstrin domain protein 2 (FARP2)-mediated Rac1 activation.…”

“…44,45 Rnd1-PlexAs interactions stimulate PlexAs GAP activity toward R-Ras by releasing or terminating inhibitory interactions within the plexin cytoplasmic region. 46,47 Plexin-induced inhibition of PI3K-Akt signaling prevents the inactivation of the serine/2hreonine kinase glycogen synthase kinase-3b (GSK-3b), thus promoting the phosphorylation and inactivation of CRMP2. Sema3A also activates Src type tyrosine kinase Fyn, thereby leading to sequential phosphorylation of CRMP2 by Cdk5 and GSK3b to regulate axon guidance and dendritic development.…”