Deletion of RIC8A in neural precursor cells leads to altered neurogenesis and neonatal lethality of mouse

Abstract

RIC8A is a noncanonical guanine nucleotide exchange factor for a subset of Gα subunits. RIC8A has been reported in different model organisms to participate in the control of mitotic cell division, cell signalling, development and cell migration. Still, the function of RIC8A in the mammalian nervous system has not been sufficiently analysed yet. Adult mice express RIC8A in the brain regions involved in the regulation of memory and emotional behaviour. To elucidate the role of RIC8A in mammalian neurogenesis we have inactivated Ric8a in neural precursor cells using Cre/Lox system. As a result, the conditional knockout mice were born at expected Mendelian ratio, but died or were cannibalized by their mother within 12 h after birth. The cerebral cortex of the newborn Nes;Ric8a(CKO) mice was thinner compared to littermates and the basement membrane was discontinuous, enabling migrating neurons to invade to the marginal zone. In addition, the balance between the planar and oblique cell divisions was altered, influencing the neuron production. Taken together, RIC8A has an essential role in the development of mammalian nervous system by maintaining the integrity of pial basement membrane and modulating cell division.

Targeted deletion of RIC8A in mouse neural precursor cells interferes with the development of the brain, eyes, and muscles

“…The findings presented here, together with our previously published results (Kask et al, ), strongly suggest that RIC8A has an essential role in the development of both central and peripheral nervous system. On the cellular level, RIC8A probably participates in the assembly and maintenance of the BM and in morphogenetic changes of cells—events that require appropriate organization of actin cytoskeleton.…”

“…Taken together, this study, together with recently published reports (Kask et al, ; Ma et al, ), strongly suggest that RIC8A is one of the key factors governing the development of the nervous system, and being indispensable in cortical morphogenesis, angiogenesis, and in the generation of the neural crest cell‐derived structures.…”

“…Although NestinCre‐recombinase and RIC8A are not expressed in skeletal muscles (Fig. A,B) of the murine embryo, newborn Nes;Ric8a CKO pups still had a neuromuscular phenotype (Kask et al, ). Thus, we prepared histological sections to measure the diameter of the skeletal muscle fibers of P0 Nes;Ric8a CKO and control mice and, as expected, found that the skeletal muscle fibers of the control mice ( n = 4) were properly arranged into fascicles (Fig.…”

“…To evaluate the role of RIC8A in the formation of breaches in basement membrane (BM) and cortical ectopias, we used conditional knockout mice where Ric8a was deleted from neural precursor cells (characterized in our previous study; Kask et al, 2015). We first focused our attention on meningeal morphology as several case studies have revealed thickening of meninges as a clinical symptom of congenital muscular dystrophies (CMD) (Hartmann et al, 1999;Nabi et al, 2003;Pabuscu et al, 2003;Yoshioka and Higuchi, 2005;Saito, 2006;Bouchet et al, 2007;Hehr et al, 2007;Yoshioka et al, 2008;Brasseur-Daudruy et al, 2012;Lach and Arredondo, 2013).…”

“…Our next aim was to analyze the skeletal muscle fibers in the Nes;Ric8a CKO mice, as newborn Nes;Ri-c8a CKO pups showed a strong neuromuscular phenotype (Kask et al, 2015) similar to that of congenital muscular dystrophies (Belpaire-Dethiou et al, 1999;Pabuscu et al, 2003). Also, our previous study showed that the inactivation of RIC8A in postmitotic neurons caused neuromuscular phenotype and severe muscle fiber atrophy (Ruisu et al, 2013).…”