STK25 and MST3 Have Overlapping Roles to Regulate Rho GTPases during Cortical Development
Year: 2021
Type: article
Abstract: Precise control of neuronal migration is required for the laminar organization of the neocortex and critical for brain function. We previously reported that the acute disruption of theStk25gene (Stk25conditional knock-out; cKO) during mouse embryogenesis causes anomalous neuronal migration in the neocortex, but paradoxically theStk25cKO did not have a cortical phenotype, suggesting some forms of compensation exist. In this study, we report that MST3, another member of the GCKIII subgroup of the Ste20-like kinase family, compensates for loss ofStk25and vice versa with sex independent manner. MST3 overexpression rescued neuronal migration deficit and abnormal axonogenesis inStk25cKO brains. Mechanistically, STK25 leads to Rac1 activation and reduced RhoA levels in the developing brain, both of which are required to fully restore neuronal migration in theStk25cKO brain. Abnormal migration phenotypes are also rescued by overexpression of Bacurd1and Cul3, which target RhoA for degradation, and activate Rac1. This study reveals that MST3 upregulation is capable of rescuing acuteStk25deficiency and resolves details of signaling downstream STK25 required for corticogenesis both common to and distinct from MST3 signaling. SIGNIFICANCE STATEMENTProper neuronal migration during cortical development is required for normal neuronal function. Here, we show that STK25 and MST3 kinases regulate neuronal migration and polarization in a mutually compensatory manner. Furthermore, STK25 balances Rac1 activity and RhoA level through forming complexes with α-PIX and β-PIX, GTPase regulatory enzymes, and Cullin3-Bacurd1/Kctd13, a pair of RhoA ubiquitination molecules in a kinase activity-independent manner. Our findings demonstrate the importance of overlapping and unique roles of STK25 and MST3 to regulate Rho GTPase activities in cortical development.
Source: Journal of Neuroscience
Authors: Tohru Matsuki, Akio Iio, Masashi Ueda, Yumi Tsuneura, Brian W. Howell, Atsuo Nakayama
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Awards: Analysis of Molecular Pathogenesis Caused by Altered Expression of Autism-Susceptibility Gene, NLGN4X., Epigenetic regulation of autism-susceptibility gene, NLGN4X., Roles of Golgi apparatus dynamics regulated by Reelin signaling in neuronal homeostasis, Generation of iPS cells from dental pulp of autism patients, miRNA administration therapy for Rett syndrome model mice, Roles of Golgi deployment regulated by Reelin-Dab1 signaling in brain development, Role of Reelin regulating Golgi apparatus dynamics in neuronal development
OpenAlex ID: W3199399157