CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling

Abstract

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins is key to development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating Semaphorin 3A (Sema3A) signaling and its dysfunction has been linked to schizophrenia, however, nothing is known about its role in the synapse pruning. Here, using newly generated crmp2 -/mice we demonstrate that while CRMP2 has only a moderate effect on Sema3A-dependent axon guidance in vivo, it is essential for Sema3F-dependent axon pruning and dendritic spine remodeling. We first demonstrate that CRMP2 deficiency interferes with Sema3A signaling in compartmentalized neuron cultures and leads to a mild defect in axon guidance in peripheral nerves and corpus callosum. Strikingly, we show that crmp2 -/mice display more prominent defects in dendritic spine pruning and stereotyped axon pruning in hippocampus and visual cortex consistent with impaired Sema3F signaling and with autism spectrum disorder (ASD)rather than schizophrenia-like phenotype. Indeed, we demonstrate that CRMP2 mediates Sema3Finduced axon retraction in primary neurons and that crmp2 -/mice display early postnatal behavioral changes linked to ASD. In conclusion, we demonstrate that CRMP2 is an essential mediator of Sema3F-dependent synapse pruning and its dysfunction in early postnatal stages shares histological and behavioral features of ASD.

Regulation of axon pruning of mossy fiber projection in hippocampus by CRMP2 and CRMP4

“…The quantification of their length indicated defective IPB pruning in CRMP4-/-mice (Figure 1). Our analysis of CRMP2-/-mice showed IPB pruning defects, as previously reported (Ziak et al, 2020) (Supporting information Figure S1). We also analyzed IPB in CRMP1-/-; CRMP2-/-DKO mice and found no additive effect on abnormalities in IPB pruning in CRMP2-/-mice (Supporting information Figure S1).…”

“…Previous studies have demonstrated the involvement of Sema3F-Nrp2 signaling in IPB pruning (Bagri et al, 2003;Sahay et al, 2003). Ziak et al (2020) showed that CRMP2deficient hippocampal neurons lacked a repellent response against Sema3F. Thus, we analyzed the genetic interaction between Nrp2 and CRMP4 and between CRMP2 in IPB pruning.…”

“…Previous studies have reported IPB pruning defects in CRMP2-/- (Ziak et al, 2020) and CRMP3-/-mice (Quach et al, 2018). To investigate the effect of the loss of CRMP1 and CRMP4 on hippocampal projection, we first stained hippocampal sections from male and female wild-type (WT), CRMP1-/-, and CRMP4-/-mice at 7−8 weeks old with a nti-calbindin antibody, which stained mossy fibers from DG to CA3.…”

“…Each CRMP displays spatiotemporal expression patterns that are precisely and differently regulated during brain development (Wang & Strittmatter 1996). CRMPs were originally identified as intracellular proteins that transduce semaphorin signaling, and the pruning defects of IPB were reported in CRMP3-/- (Quach et al, 2018) and CRMP2-/-mice (Ziak et al, 2020). The expressions of CRMP1 and CRMP4 in the developing mouse brain overlaps with those of CRMP2 and CRMP3; however, the involvement of CRMP1 and CRMP4 in IPB pruning remains unclear.…”

Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions

“…Interestingly, Fyn promotes semaphorin receptor (plexin) phosphorylation and facilitates semaphorin and plexin interaction [ 111 , 112 , 113 ] that is crucial in mediating events related to neuronal polarization and migration [ 114 , 115 ], synapse formation [ 116 , 117 ], axonal pruning [ 118 , 119 ] and dendritic arborization [ 120 , 121 , 122 ] ( Figure 4 ).…”