Abstract
Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In this study, we analyzed mouse Plekhg2 function during cortical development, both in vitro and in vivo. The p.Arg200Trp variant in mouse (Plekhg2-RW), which corresponds to the p.Arg204Trp variant in humans, showed decreased guanine nucleotide-exchange activity for Rac1, Rac3, and Cdc42. Acute knockdown of Plekhg2 using in utero electroporation-mediated gene transfer did not affect the migration of excitatory neurons during corticogenesis. On the other hand, silencing Plekhg2 expression delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and p21-activated kinase 1 signaling pathways. This phenotype was rescued by expressing an RNAi-resistant version of wildtype Plekhg2, but not of Plekhg2-RW. Axon pathfinding was also impaired in vitro and in vivo in Plekhg2-deficient cortical neurons. At P14, knockdown of Plekhg2 was observed to cause defects in dendritic spine morphology formation. Collectively, these results strongly suggest that PLEKHG2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEKHG2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders.
Highlights
Rho family guanosine triphosphatases (GTPases) are known to regulate various cellular processes, such as morphology, gene transcription, proliferation, and migration through actin cytoskeletal rearrangement, and they play crucial roles in various cell types [1,2,3,4]. to other GTPases, Rho family proteins are binary switches that cycle between an inactive (GDP-bound) and an active (GTP-bound) conformational state
When we examined the role of Plekhg2 in dendritic arbor formation, introduction of sh-Plek2#1 and #2 (1.0 μg) into the ventricular zone (VZ) cells at E14.5 resulted in highly suppressed dendritic arborization at postnatal day 7 (P7) (Figure 2B)
Since Plekhg2 was shown to be involved in dendrite network formation, we further explored whether Plekhg2 participates in the synapse formation and/or maintenance
Summary
Rho family guanosine triphosphatases (GTPases) are known to regulate various cellular processes, such as morphology, gene transcription, proliferation, and migration through actin cytoskeletal rearrangement, and they play crucial roles in various cell types [1,2,3,4]. to other GTPases, Rho family proteins are binary switches that cycle between an inactive (GDP-bound) and an active (GTP-bound) conformational state. PLEKHG2 (Pleckstrin homology and RhoGEF domain containing G2), which is a GEF for Rac and Cdc, interacts with Gβγ subunits of heterotrimeric G proteins and is activated upon co-expression of Gβγ in various cell types; whether activation is mediated directly by Gβγ remains to be clarified [8,9,10,11,12]. Rac and Cdc are crucial for the spatiotemporal activation of various effectors to control cell morphology through cytoskeletal organization, and they have been reported to be important for the cortical neuron development [13,14,15,16,17,18]
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