The Neuron Navigators: Structure, function, and evolutionary history

Abstract

Neuron navigators (Navigators) are cytoskeletal-associated proteins important for neuron migration, neurite growth, and axon guidance, but they also function more widely in other tissues. Recent studies have revealed novel cellular functions of Navigators such as macropinocytosis, and have implicated Navigators in human disorders of axon growth. Navigators are present in most or all bilaterian animals: vertebrates have three Navigators (NAV1-3), Drosophila has one (Sickie), and Caenorhabditis elegans has one (Unc-53). Structurally, Navigators have conserved N- and C-terminal regions each containing specific domains. The N-terminal region contains a calponin homology (CH) domain and one or more SxIP motifs, thought to interact with the actin cytoskeleton and mediate localization to microtubule plus-end binding proteins, respectively. The C-terminal region contains two coiled-coil domains, followed by a AAA+ family nucleoside triphosphatase domain of unknown activity. The Navigators appear to have evolved by fusion of N- and C-terminal region homologs present in simpler organisms. Overall, Navigators participate in the cytoskeletal response to extracellular cues via microtubules and actin filaments, in conjunction with membrane trafficking. We propose that uptake of fluid-phase cues and nutrients and/or downregulation of cell surface receptors could represent general mechanisms that explain Navigator functions. Future studies developing new models, such as conditional knockout mice or human cerebral organoids may reveal new insights into Navigator function. Importantly, further biochemical studies are needed to define the activities of the Navigator AAA+ domain, and to study potential interactions among different Navigators and their binding partners.

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

“…Nav2 encodes Neuron navigator 2, a cytoskeletal associated protein important for cortical neuron migration and axon growth (Powers et al 2022). Bi-allelic loss-of-function of NAV2 was reported to cause a neurodevelopmental disorder with a complex brain malformation (Accogli et al 2023).…”

“…Dbx1 encodes Developing brain homeobox 1, a transcription factor critical for interneuron differentiation, including Cajal Retzius cells in the cortex and brainstem pre-Bötzinger complex interneurons (Akins et al 2017; Powers et al 2022; Vann et al 2018). Interestingly, the pre-Bötzinger complex is a critical nucleus for generating respiratory rhythms and has been implicated in SUDEP (Akins et al 2017; George et al 2023; Xia et al 2016).…”

Downregulation of miR-29a as a possible diagnostic biomarker for schizophrenia

“…Downregulation of miR-29a is associated with increased level of NAV3 in Alzheimer disease brains [ 28 ]. Since NAV3 has is part of neural navigator gene family like NAV1 and NAV 2, dysregulation in NAV 3 expression can lead to abnormal neural growth and play a role is disease such as autism spectrum disorders [ 29 ] or Alzheimer disease.…”

Establishment of the Myeloid TBX-Code Reveals Aberrant Expression of T-Box Gene TBX1 in Chronic Myeloid Leukemia

“…Furthermore, TMEM38A regulates the development of muscle cells via organization of the nuclear peripheral region [ 61 ], which may also play a role in myeloid differentiation. Finally, NAV1 encodes a cytoskeletal-associated protein is highly expressed in the heart [ 62 ], suggesting that TBX1 may regulate NAV1 in this tissue ( Figure S11 ). Our data revealed additional elevated NAV1 expression levels in DCs ( Figure S11 ).…”