{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:17:17Z","timestamp":1781284637648,"version":"3.54.1"},"reference-count":54,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K1569400"],"award-info":[{"award-number":["24K1569400"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Zinc (Zn\n                    <jats:sup>2+<\/jats:sup>\n                    ), an essential trace element, has been increasingly recognized for its crucial role in neural development and regeneration. Although its function in central nervous system neurogenesis is well documented, its involvement in parasympathetic innervation remains insufficiently characterized. In this study, we examined the neurochemical interplay between Zn\n                    <jats:sup>2+<\/jats:sup>\n                    and the neurotrophic factor neurturin (NRTN) during submandibular salivary gland (SMG) development, with particular emphasis on the PI3K\/AKT signaling axis involved in parasympathetic innervation. Employing an ex\u00a0vivo embryonic mouse SMG organ culture system combined with a bioengineered agarose\u2010based hydrogel for sustained Zn\n                    <jats:sup>2+<\/jats:sup>\n                    delivery, we demonstrate that zinc supplementation markedly enhances both epithelial branching morphogenesis and neurite outgrowth. Mechanistic investigations revealed that Zn\n                    <jats:sup>2+<\/jats:sup>\n                    activates the PI3K\/AKT pathway and promotes epithelial and neuronal development, even in the presence of pharmacological inhibitors targeting PI3K or AKT. NRTN, a critical neurotrophic factor implicated in parasympathetic innervation, was identified as an upstream activator of AKT, and its signaling activity was substantially enhanced by Zn\n                    <jats:sup>2+<\/jats:sup>\n                    . Notably, co\u2010administration of Zn\n                    <jats:sup>2+<\/jats:sup>\n                    and NRTN restored SMG morphogenesis and neuronal extension despite PI3K\/AKT pathway inhibition, indicating a robust compensatory mechanism. This synergistic interaction reveals a previously unrecognized crosstalk between metal ion\u2010mediated and neurotrophin\u2010dependent signaling pathways during peripheral organ development. Collectively, this work broadens the current understanding of zinc's biological functions beyond the central nervous system and highlights its therapeutic potential in regenerative approaches targeting salivary gland dysfunction and related disorders involving compromised autonomic innervation.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70275-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70275","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T13:35:07Z","timestamp":1761917707000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Zinc Modulates Neurturin\u2013\n                    <scp>AKT<\/scp>\n                    Signaling to Promote Parasympathetic Innervation in Developing Submandibular Salivary Glands"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5124-0376","authenticated-orcid":false,"given":"Gulsan Ara Sathi","family":"Kazi","sequence":"first","affiliation":[{"name":"Graduate School of Science and Engineering Yamagata University  Yamagata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Graduate School of Science and Engineering Yamagata University  Yamagata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Fujihara","sequence":"additional","affiliation":[{"name":"Graduate School of Science and Engineering Yamagata University  Yamagata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Migita","sequence":"additional","affiliation":[{"name":"Graduate School of Science and Engineering Yamagata University  Yamagata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bashir","family":"Ahmmad","sequence":"additional","affiliation":[{"name":"Graduate School of Science and Engineering Yamagata University  Yamagata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.5607\/en.2014.23.3.200"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2015786118"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.03.020"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.11.052"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2761"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bioeng.6.040803.140040"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.04.083"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21238941"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.61.070192.004341"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.4507"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20211"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.044"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/neu.1037"},{"issue":"3","key":"e_1_2_11_15_1","first-page":"175","article-title":"Wolff's Law and Bone's Structural Adaptations to Mechanical Usage: An Overview for Clinicians","volume":"64","author":"Frost H. 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