Abstract
Previous research has demonstrated that the collapsin response mediator protein (CRMP) family is involved in the formation of neural networks. A recent whole-exome sequencing study identified a de novo variant (S541Y) of collapsin response mediator protein 4 (CRMP4) in a male patient with autism spectrum disorder (ASD). In addition, Crmp4-knockout (KO) mice show some phenotypes similar to those observed in human patients with ASD. For example, compared with wild-type mice, Crmp4-KO mice exhibit impaired social interaction, abnormal sensory sensitivities, broader distribution of activated (c-Fos expressing) neurons, altered dendritic formation, and aberrant patterns of neural gene expressions, most of which have sex differences. This review summarizes current knowledge regarding the role of CRMP4 during brain development and discusses the possible contribution of CRMP4 deficiencies or abnormalities to the pathogenesis of ASD. Crmp4-KO mice represent an appropriate animal model for investigating the mechanisms underlying some ASD phenotypes, such as impaired social behavior, abnormal sensory sensitivities, and sex-based differences, and other neurodevelopmental disorders associated with sensory processing disorders.
Highlights
The formation of neural networks is temporally and spatially regulated by numerous molecules, such as extracellular molecules regulating cell adhesion and axon guidance, and intracellular signaling molecules regulating axon elongation and the formation of dendrites, spines, and synapses
In the social interaction test, male Crmp4-KO mice spent significantly less time actively interacting with a stranger mouse than male wild type (WT) littermates, there were no significant differences in the amount of active interaction between WT and Crmp4-KO females
These findings indicate that male-dominant impairments in social behavior can be observed in Crmp4-KO mice [8]
Summary
The formation of neural networks is temporally and spatially regulated by numerous molecules, such as extracellular molecules regulating cell adhesion and axon guidance, and intracellular signaling molecules regulating axon elongation and the formation of dendrites, spines, and synapses. Collapsin response mediator proteins (CRMPs) are intracellular signaling molecules elicited by extracellular signals (e.g., semaphorin (Sema) 3A and reelin) during neuronal migration, differentiation, neurite network organization, and even remodeling [1,2,3]. Genome-wide studies, genetic linkage analyses, proteomic analyses, and translational approaches have revealed altered expression levels of CRMPs in neurodevelopmental disorders, such as schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) [3,4,5,6,7,8]. During the past decade, many studies using knockout (KO) mice have demonstrated the role of CRMPs in the pathogenesis of neurodevelopmental disorders, as described in Section 3 below. In our recent whole-exome sequencing study, we identified a de novo variant of CRMP4 in a male patient with ASD [8]. We discuss the functions of CRMP4 in the developing brain and the possible involvement of CRMP4 deficiencies and abnormalities in the pathogenesis of neurodevelopmental disorders
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