Deletion of collapsin response mediator protein 4 results in abnormal layer thickness and elongation of mitral cell apical dendrites in the neonatal olfactory bulb

Abstract

Collapsin response mediator protein 4 (CRMP4), a member of the CRMP family, is involved in the pathogenesis of neurodevelopmental disorders such as schizophrenia and autism. Here, we first compared layer thickness of the olfactory bulb between wild-type (WT) and CRMP4-knockout (KO) mice. The mitral cell layer (MCL) was significantly thinner, whereas the external plexiform layer (EPL) was significantly thicker in CRMP4-KO mice at postnatal day 0 (PD0) compared with WTs. However, differences in layer thickness disappeared by PD14. No apoptotic cells were found in the MCL, and the number of mitral cells (MCs) identified with a specific marker (i.e. Tbx21 antibody) did not change in CRMP4-KO neonates. However, DiI-tracing showed that the length of mitral cell apical dendrites was greater in CRMP4-KO neonates than in WTs. In addition, expression of CRMP4 mRNA in WT mice was most abundant in the MCL at PD0 and decreased afterward. These results suggest that CRMP4 contributes to dendritic elongation. Our in vitro studies showed that deletion or knockdown of CRMP4 resulted in enhanced growth of MAP2-positive neurites, whereas overexpression of CRMP4 reduced their growth, suggesting a new role for CRMP4 as a suppressor of dendritic elongation. Overall, our data suggest that disruption of CRMP4 produces a temporary alteration in EPL thickness, which is constituted mainly of mitral cell apical dendrites, through the enhanced growth of these dendrites.

Human CRMP4 mutation and disrupted Crmp4 expression in mice are associated with ASD characteristics and sexual dimorphism

“…We and others have previously reported that the deficiency of Crmp4 affects dendritic morphology 18 , 19 . In addition, there have been several recent reports demonstrating altered dendritic development in ASD mouse models 20 , 21 , leading us to focus on dendritic development in the present study.…”

“…Some studies have shown that CRMP4 negatively regulates axonal growth 57 – 60 , while others have shown its positive regulation of axonal elongation 61 , 62 . In addition, CRMP4 is involved in dendrite formation 18 , 19 , 63 . In our study, we confirmed that CRMP4 suppresses the length of dendrites and number of dendritic branches (Fig.…”

CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury

“…In Crmp4−/− mice, proximal bifurcation of CA1 hippocampal pyramidal neurons were seen in the same manner as in Sema3a−/− mice [56] and p35−/− mice, a Cdk5 activator [57]. Tissue structure abnormalities and neuronal hyperactivity due to the enhanced dendritic growth of mitral cells in the olfactory bulb was also observed in Crmp4−/− mice [58,59]. Likewise, a decrease in axon growth of hippocampal neurons was also seen in Crmp4−/− mice [60].…”

“…For example, in Crmp4−/− mice, enhanced dendrite growth results in the hyperactivity of neurons in the olfactory bulb [58,59], and reduced spine density is observed in Crmp2KI/KI mice [50]. Likewise, the increase in the amount of dopamine secreted in Crmp1−/− mice leads to hyperactivity-exhibiting a neuropsychiatric disease-like phenotype.…”

“…Crmp4-/-Increased proximal bifurcation of CA1 pyramidal neurons [57] Axon growth and motor and sensory recovery after SCI [41,88] Enhanced dendritic growth and hyperactivity in olfactory bulb neurons [58,59] Reduced apoptosis, inflammation, and scar formation [41] Decrease in axon extension and growth cone formation [60] Delayed dopaminergic neuron death in the PD model [43] …”