Autism spectrum disorder susceptibility gene TAOK2 affects basal dendrite formation in the neocortex

Abstract

How neurons develop their morphology is an important question in neurobiology. Here we describe a novel pathway that specifically affects the formation of basal dendrites and axonal projections in cortical pyramidal neurons. We report that thousand-and-one-amino acid 2 (TAO2) kinase plays an essential role in dendrite morphogenesis. TAO2 down-regulation impairs basal dendrite formation in vivo without affecting apical dendrites. Moreover, TAO2 interacts with Neuropilin 1 (Npn1), a receptor protein that binds the secreted guidance cue Semaphorin 3A (Sema3A). TAO2 over-expression restores dendrite formation in cultured cortical neurons from Npn1Sema− mice, which express Npn1 receptors incapable of binding Sema3A. TAO2 over-expression also ameliorates the basal dendrite impairment resulting from Npn1 down-regulation in vivo. Finally, Sema3A and TAO2 modulate the formation of basal dendrites through the activation of the c-Jun N-Terminal Kinase (JNK). These results delineate a pathway whereby Sema3A and Npn1 transduce signals through TAO2 and JNK to regulate basal dendrite development in cortical neurons.

Cellular Phenotypes in Human iPSC-Derived Neurons from a Genetic Model of Autism Spectrum Disorder

“…For example, MVP binds PTEN and functions as a scaffold protein for ERK, encoded by MAPK3 , and hence may regulate the PI3K/AKT and Ras/MAPK pathways(Kolli et al, 2004; Yu et al, 2002). Another candidate, TAOK2, activates the Ras/MAPK pathway and has been shown to regulate basal dendrite formation in cortical neurons(Calderon de Anda et al, 2012). Mutations in the Ras/MAPK pathway are known to cause NDDs (RASopathies) and have macrocephaly as one of the clinical symptoms(Rauen, 2013).…”

“…We hypothesize that perturbation of one or more of these cellular processes may underlie the brain growth phenotype in 16p11.2 CNV carriers, given that the CNV harbors genes known to manifest early neurobiological phenotypes when dysregulated. Noteworthy examples are: MAPK3 , a key component of the Ras/MAPK pathway which regulates multiple processes including proliferation and differentiation, TAOK2, a kinase essential for dendrite and spine morphogenesis and KCTD13 , a ubiquitin ligase family member shown to affect head size by altering NPC proliferation and apoptosis in a dose-dependent manner in zebrafish (Calderon de Anda et al, 2012; Golzio and Katsanis, 2013; Pucilowska et al, 2015; Yadav et al, 2017). However, the cellular mechanisms in 16p11.2 CNV-carriers underlying macro- or microcephaly remain unknown.…”

Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

“…Knockdown and overexpression studies have attempted to model these gene dosage changes, implicating two genes, Kctd13 and Taok2, in altered brain size and neurite morphogenesis, respectively (de Anda et al, 2012 and Golzio et al, 2012). However, it is not known whether knockdown-mediated dosage changes accurately model loss of a single allele for each of these genes.…”

Regulation of dendrite morphogenesis by extrinsic cues

“…Recently, the protein kinase TAO kinase 2 (TAOK2) has been suggested to collaborate with NRP1 in directing Sema3A-induced basal dendrite growth [16]. Expression of TAOK2 stimulates Jun kinase (JNK) activity and thereby restores basal dendrite arborization in NRP1-deficient neurons.…”

“…Substrates of JNK that mediate Sema3A-induced basal dendrite arborization remain to be identified. Interestingly, TAOK2 is an autism spectrum disorder susceptibility gene, and deficits in basal dendrite development uponTAOK2 downregulation may mimic the underdeveloped neuron morphology associated with autism [16]. …”