Nav2 hypomorphic mutant mice are ataxic and exhibit abnormalities in cerebellar development

Abstract

Development of the cerebellum involves a coordinated program of neuronal process outgrowth and migration resulting in a foliated structure that plays a key role in motor function. Neuron navigator 2 (Nav2) is a cytoskeletal-interacting protein that functions in neurite outgrowth and axonal elongation. Herein we show that hypomorphic mutant mice lacking the full-length Nav2 transcript exhibit ataxia and defects in cerebellar development. At embryonic day (E)17.5, the mutant cerebellum is reduced in size and exhibits defects in vermal foliation. Reduction in cell proliferation at early times (E12.5 and E14.5) may contribute to this size reduction. The full-length Nav2 transcript is expressed in the premigratory zone of the external granule layer (EGL). Granule cells in the germinal zone of the EGL appear to proliferate normally, however, due to the reduction in cerebellar circumference there are fewer total BrdU-labeled granule cells in the mutants, and these fail to migrate normally toward the interior of the cerebellum. In Nav2 hypomorphs, fewer granule cells migrate out of cerebellar EGL explants and neurite outgrowth from both explants and isolated external granule cell cultures is reduced. This suggests the formation of parallel axon fibers and neuronal migration is disrupted in Nav2 mutants. This work supports an essential role for full-length Nav2 in cerebellar development, including axonal elongation and migration of the EGL neurons.

Gene expression signatures differentiate uterine endometrial stromal sarcoma from leiomyosarcoma

“…NAV2 is involved in cerebellar and cranial nerve development, as well as in blood pressure regulation [52,53]. Recently, the NAV2 gene was found to be frequently fused to the WNT pathway gene TCF7L1 in colorectal carcinoma in a study by the Cancer Genome Atlas Network [54].…”

14-3-3ε and NAV2 interact to regulate neurite outgrowth and axon elongation

“…Alternatively, NAV2 could serve a scaffolding/enzymatic role, bringing additional functional proteins to the complex, or possibly by integrating signaling cues to other components of the cytoskeleton [2]. Interestingly, LIS1-deficient cerebellar granule neurons are defective in axonal extension and neuronal migration [32], an effect also observed in EGL explants and neurons cultured from Nav2/unc53H2 hypomorphic mutant mice [3]. The present work showing that NAV2 interacts with 14-3-3ε suggests that NAV2 could participate in regulating cytoskeletal dynamics as a part of protein complexes that also contain 14-3-3ε.…”

“…Nav2/unc53H2 mutant embryos show a reduction in overall nerve fiber density, with cranial nerves IX (glossopharyngeal) and X (vagus) sometimes fused or poorly connected to the hindbrain. Additional work from our group shows that the formation of parallel axon fibers and neuronal migration is disrupted in the cerebellum of Nav2/unc53H2 hypomorphs, and that these mutants exhibit abnormal vermal foliation and ataxia [3]. …”

Unraveling the Specific Ischemic Core and Penumbra Transcriptome in the Permanent Middle Cerebral Artery Occlusion Mouse Model Brain Treated with the Neuropeptide PACAP38

“…Three molecules are of particular interest, namely, neuropilin 1( NRP1 ) [58], tectonin beta-propeller repeat containing 2 ( TECPR2 ) [59], and neuron navigator 2 ( NAV2 ) [60]. The NRP1 is a multipurpose molecule that has a role in angiogenesis, axon guidance, cell survival, migration, and invasion.…”