{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T19:26:28Z","timestamp":1789500388287,"version":"build-2803163510"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["T32-HL007446"],"award-info":[{"award-number":["T32-HL007446"]}]},{"name":"NIH","award":["F32NS092448"],"award-info":[{"award-number":["F32NS092448"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>\n                    The axon initial segment (AIS) is essential for initiating action potentials and maintaining neuronal polarity, yet the developmental roles of its core molecular components\u2014Neurofascin 186 (NF186) and Ankyrin G (AnkG)\u2014remain incompletely defined in cerebellar Purkinje cells. Here, we generated Purkinje cell-specific NF186 and AnkG single- and double-knockout mice to investigate how these adhesion and scaffolding proteins cooperatively regulate AIS formation, ion channel localization, synaptic targeting, and neuronal survival. We found that genetic ablation of either\n                    <jats:italic>Nfasc NF186<\/jats:italic>\n                    (\n                    <jats:italic>NFKO<\/jats:italic>\n                    ) or\n                    <jats:italic>Ankyrin3<\/jats:italic>\n                    (\n                    <jats:italic>AnkGKO<\/jats:italic>\n                    ) disrupted assembly and maintenance of the AIS cytoskeleton, and that this defect was exacerbated by combined loss of both proteins during postnatal development. Other AIS-enriched proteins, including \u03b2IV Spectrin (\u03b2IVSpec), voltage-gated sodium (Na\n                    <jats:sub>v<\/jats:sub>\n                    ), and potassium (K\n                    <jats:sub>v<\/jats:sub>\n                    1.2) channels, failed to properly localize to the AIS and progressively disintegrated between postnatal days 10 and 30. Notably, K\n                    <jats:sub>v<\/jats:sub>\n                    1.2 clustering at the pinceau synapse was disrupted, and basket cell axons showed misaligned terminal organization, indicating defective inhibitory synapse innervation. By 2\u202fmonths of age, degeneration of Purkinje cells was evident, accompanied by cerebellar dysfunction. Notably,\n                    <jats:italic>AnkG<\/jats:italic>\n                    ablation caused a progressive postnatal loss of NF186 at the AIS, whereas\n                    <jats:italic>NF<\/jats:italic>\n                    ablation resulted in much slower loss of AnkG at the AIS in Purkinje cells and closely phenocopied the severe AIS destabilization observed in\n                    <jats:italic>NF\/AnkG<\/jats:italic>\n                    double-knockout mice. In addition, our RNA-seq analysis revealed that Purkinje cell-specific loss of NF186 predominantly activated immune-inflammatory pathways; AnkG loss significantly disrupted neuronal developmental and metabolic processes; and the dual loss of NF186\/AnkG produced transcriptional changes that were distinct from, and in part intermediate to, those observed in NF186 and AnkG single knockout. Collectively, our results show that NF186 and AnkG have complementary, non-redundant roles in establishing and maintaining the Purkinje cell AIS, and that their loss disrupts synaptic organization at the AIS. These findings advance our understanding of AIS development in cerebellar neurons and have implications for diseases involving AIS dysfunction, including cerebellar ataxia and demyelinating neuropathies.\n                  <\/jats:p>","DOI":"10.3389\/fncel.2026.1690466","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T04:45:09Z","timestamp":1776055509000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia"],"prefix":"10.3389","volume":"20","author":[{"given":"Qian","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Long School of Medicine, University of Texas Health Science Center","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Long School of Medicine, University of Texas Health Science Center","place":["San Antonio, TX, United States"]},{"name":"Department of Neuroscience, University of Texas at Dallas","place":["Richardson, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey B.","family":"Sell","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Long School of Medicine, University of Texas Health Science Center","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manzoor A.","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Long School of Medicine, University of Texas Health Science Center","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3199","DOI":"10.1523\/JNEUROSCI.2326-22.2023","article-title":"The axon initial segment plays a dynamic role in peripheral motor neuron synapse regeneration following injury","volume":"43","author":"Adler","year":"2023","journal-title":"J. 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