Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development

Abstract

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In this study, we identified a female affected with neurodevelopmental impairment and a complex brain and cardiac malformations in which clinical exome sequencing led to the identification of NAV2 biallelic truncating variants. Through protein expression analysis and cell migration assay in patient-derived fibroblasts, we provide evidence linking NAV2 deficiency to cellular migration deficits. In model organisms, the overall CNS histopathology of the Nav2 hypomorphic mouse revealed developmental anomalies including cerebellar hypoplasia and dysplasia, corpus callosum hypo-dysgenesis, and agenesis of the olfactory bulbs. Lastly, we show that the NAV2 ortholog in Drosophila, sickie (sick) is widely expressed in the fly brain, and sick mutants are mostly lethal with surviving escapers showing neurobehavioral phenotypes. In summary, our results unveil a novel human neurodevelopmental disorder due to genetic loss of NAV2, highlighting a critical conserved role of the NAV2 gene in brain and cerebellar development across species.

The Neuron Navigators: Structure, function, and evolutionary history

“…Furthermore, granule cell migration was impaired in hypomorphic cerebella in vivo, and migration and neurite outgrowth defects were observed in cerebellar explants from the knockout mice (McNeill et al, 2011). A more recent paper also observed a reduction of cerebellar size in these mice, including abnormalities in the development of the VIa and VIb/VII lobes, as well as a thin corpus collosum, and size reduction in the thalamus and hypothalamus (Accogli et al, 2022). All of these phenotypes demonstrate that Nav2 plays an essential role in neuron migration and morphogenesis of several areas of developing brain.…”

“…Previous studies found that Navigators and their invertebrate homologs have AAA+ nucleotide triphosphatase (NTPase), calponin homology (CH), and coiled-coil (CC) domains, with the exception that NAV1 lacks the CH domain, likely due to secondary loss ( Maes et al, 2002 ; Peeters et al, 2004 ; Stringham and Schmidt, 2009 ; Abe et al, 2014 ; Accogli et al, 2022 ). However, those differ in the number of reported CC domains (2, 3, or 4), and in the reported presence or absence of conserved microtubule- or cytoskeletal-binding domains.…”

“…The potent activation of Nav2 by Pax6, Tbr2, and Tbr1 implicates Nav2 as particularly important for cortical neuron development. Indeed, Nav2 hypomorphic mutant mice have a small corpus callosum (a major cortical axon tract), and a human patient with Nav2 mutations displayed cortical dysgyria (a neuronal migration disorder), as well as hypoplasia of the corpus callosum and anterior commissure, among other abnormalities ( Accogli et al, 2022 ).…”

“…In D. melanogaster , sickie loss of function mutants have been characterized in a few papers, providing insight into the processes in which the Navigators may be involved ( Abe et al, 2014 ; Walkinshaw et al, 2015 ; Accogli et al, 2022 ). The first paper describes a mutant that lacks a 510 amino acid region containing a proline rich-region and a coiled-coil domain in one allele, and a transposon inserted into that same region in the second allele ( Abe et al, 2014 ).…”

“…This mutant displayed abnormalities in brain formation in the central lobe and mushroom bodies, which were attributed to defects in axon growth ( Abe et al, 2014 ). A Drosophila loss of function mutant described in Accogli et al ( Accogli et al, 2022 ) introduced a cassette between sickie exons 10 and 11 into one allele. The resulting mutant heterozygotes were semi-lethal, and displayed motor defects and heat-induced seizures ( Accogli et al, 2022 ), suggestive of neurological dysfunction.…”