Regulators of Rho GTPases in the Nervous System: Molecular Implication in Axon Guidance and Neurological Disorders

Abstract

One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the complex environment of a developing embryo toward their targets, which can be far away from their cell bodies. Successful implementation of neuronal wiring, which is crucial for fulfillment of all behavioral functions, is achieved through an intimate interplay between axon guidance and neural activity. In this review, our focus will be on axon pathfinding and the implication of some of its downstream molecular components in neurological disorders. More precisely, we will talk about axon guidance and the molecules implicated in this process. After, we will briefly review the Rho family of small GTPases, their regulators, and their involvement in downstream signaling pathways of the axon guidance cues/receptor complexes. We will then proceed to the final and main part of this review, where we will thoroughly comment on the implication of the regulators for Rho GTPases—GEFs (Guanine nucleotide Exchange Factors) and GAPs (GTPase-activating Proteins)—in neurological diseases and disorders.

Regulators of H3K4 methylation mutated in neurodevelopmental disorders control axon guidance in Caenorhabditis elegans

“…7 ), and that a disease-associated mutation of SETD1B reproduces the axonal phenotype in the nematode, our studies provide evidence for a common denominator among these genes. Altogether, our results suggest that aberrant axon guidance is a shared trait in neurodevelopmental diseases and offer experimental support to a recently suggested hypothesis proposing that dysregulated axonal guidance underlines neurological disorders ( Van Battum et al, 2015 ; Niftullayev and Lamarche-Vane, 2019 ; McFadden and Minshew, 2013 ).…”

Deletion of the Nucleotide Exchange Factor Vav3 Enhances Axonal Complexity and Synapse Formation but Tampers Activity of Hippocampal Neuronal Networks In Vitro

“…Interestingly, cerebellar development is altered in Vav3 −/− mice. Behavioural experiments revealed deficits concerning motor coordination and gaiting during the early postnatal period of Vav3 −/− mice that ameliorated in older animals [20,52].…”

Rho GTPases in the Amygdala—A Switch for Fears?

“…Cdc42 was found to be upregulated in the prefrontal cortex of schizophrenic patients [131] and several other Rho effectors have been reported to be associated with schizophrenia, such as Kalirin, known as ArhGEF24, ArhGEF11, ArhGAP18, ArhGAP33, Myosin lXb, and Chimerin 2 [15,132,133]. Nevertheless, they are yet to be studied in animal models.…”

“…Importantly, Rho GTPases are also expressed in the amygdala. There, Rho GTPases and their effectors [ 14 ] participate in biological processes regulating fear conditioning in relation to neuropsychiatric disorders [ 15 , 16 ].…”