The regulatory and enzymatic functions of CRMPs in neuritogenesis, synaptic plasticity, and gene transcription

Abstract

Collapsin response mediator proteins (CRMPs) are ubiquitously expressed in neurons from worms to humans. A cardinal feature of CRMPs is to mediate growth cone collapse in response to Semaphorin-3A signaling through interactions with cytoskeletal proteins. These are critical regulatory roles that CRMPs play during neuritogenesis and neural network formation. Through post-translational modifications, such as phosphorylation, O-GlcNAcylation, SUMOylation, and proteolytic cleavage, CRMPs participate in synaptic plasticity by modulating NMDA receptors, L- and N-type voltage-gated calcium channels (VGCCs), thus affecting neurotransmitter release. CRMPs also possess histone deacetylase (HDAC) activity, which deacetylates histone H4 during neuronal death. Calcium-dependent proteolytic cleavage of CRMPs results in the truncation of CRMPs, producing a large 54 kD fragment (p54). Translocation of the p54 fragment into the nucleus leads to deacetylation of nuclear histone H4 and de-repression of transcription factor E2F1 expression. Increased expression of E2F1 elevates the expression of genes in cell cycle and death. These new and exciting studies lead to the realization that CRMPs are multifunctional proteins with both regulatory and enzymatic functions. Increasing numbers of studies associate these functions of CRMPs with the development of mental and neurological disorders, such as schizophrenia, Alzheimer's diseases, brain trauma, and stroke. This review focuses on new evidence showing the regulatory and enzymatic functions of CRMPs and highlights recent understandings of CRMPs' roles in neurological diseases.

Keywords: Collapsin response mediator proteins; Histone H4 deacetylase; Mental disorders; Neurological disease; Neuronal guidance; Stroke.