The atypical Rho GTPase Rnd2 is critical for dentate granule neuron development and anxiety-like behavior during adult but not neonatal neurogenesis

Abstract

Despite the central role of Rho GTPases in neuronal development, their functions in adult hippocampal neurogenesis remain poorly explored. Here, by using a retrovirus-based loss-of-function approach in vivo, we show that the atypical Rho GTPase Rnd2 is crucial for survival, positioning, somatodendritic morphogenesis, and functional maturation of adult-born dentate granule neurons. Interestingly, most of these functions are specific to granule neurons generated during adulthood since the deletion of Rnd2 in neonatally-born granule neurons only affects dendritogenesis. In addition, suppression of Rnd2 in adult-born dentate granule neurons increases anxiety-like behavior whereas its deletion in pups has no such effect, a finding supporting the adult neurogenesis hypothesis of anxiety disorders. Thus, our results are in line with the view that adult neurogenesis is not a simple continuation of earlier processes from development, and establish a causal relationship between Rnd2 expression and anxiety.

Investigating the Protective Effects of a Citrus Flavonoid on the Retardation Morphogenesis of the Oligodendroglia-like Cell Line by Rnd2 Knockdown

“…In contrast, the functional loss of Rnd2 and the possible effector signaling molecules underlying Rnd2 are related to some diseases including neuropsychiatric disorders, which are often associated with abnormalities of oligodendroglial differentiation and myelination and neuronal differentiation [ 6 , 7 , 8 ]. Rnd2 is weakly but specifically expressed in cortical plates in embryos and in some neuronal cells of the hippocampal regions in adults [ 51 , 52 ].…”

“…The molecules underlying neuropsychiatric disorders include small GTPases, some of which mediate cell morphological changes. Rnd2 is one such small GTPase, belonging to an atypical member of the Rho family small GTPase, and loss of function or functional inhibition of Rnd2 may be related to their disorders [ 5 , 6 , 7 , 8 ]. Similar to Ras GTPases, Rho GTPases are generally bound to GTP or GDP.…”

Does the plasticity of neural stem cells and neurogenesis make them biosensors of disease and damage?

“…This aspect has been much less addressed, but when addressed, modified morphology changes were found to be accompanied by functional changes ( Duan et al, 2007 ; Fitzsimons et al, 2013 ; Kerloch et al, 2021 ). Several molecular mechanisms have been found to regulate the differentiation, at least in terms of morphological development of newborn neurons, such as disrupted-in-schizophrenia-1 ( Duan et al, 2007 ); Rho GTPase Rnd2 ( Kerloch et al, 2021 ) and glycogen synthase kinase-3β glycogen synthase kinase-3β ( Llorens-Martín et al, 2013 ). What is the role of these mechanisms, and what others could be involved, in disease-induced newborn neuron dystrophy remains to be fully explored.…”