{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T13:15:24Z","timestamp":1792242924002,"version":"4.4.0"},"reference-count":50,"publisher":"The Company of Biologists","issue":"15","license":[{"start":{"date-parts":[[2017,2,1]],"date-time":"2017-02-01T00:00:00Z","timestamp":1485907200000},"content-version":"vor","delay-in-days":184,"URL":"http:\/\/www.biologists.com\/user-licence-1-1"}],"funder":[{"name":"Northeastern University;"},{"name":"Howard Hughes"},{"name":"Medical Institute"},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1558017"],"award-info":[{"award-number":["1558017"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,8,1]]},"abstract":"<jats:p>The Mexican axolotl (Ambystoma mexicanum) is capable of fully regenerating amputated limbs, but denervation of the limb inhibits the formation of the post-injury proliferative mass called the blastema. The molecular basis behind this phenomenon remains poorly understood, but previous studies have suggested that nerves support regeneration via the secretion of essential growth-promoting factors. An essential nerve-derived factor must be found in the blastema, capable of rescuing regeneration in denervated limbs, and its inhibition must prevent regeneration. Here, we show that the neuronally secreted protein Neuregulin-1 (NRG1) fulfills all these criteria in the axolotl. Immunohistochemistry and in situ hybridization of NRG1 and its active receptor ErbB2 revealed that they are expressed in regenerating blastemas but lost upon denervation. NRG1 was localized to the wound epithelium prior to blastema formation and was later strongly expressed in proliferating blastemal cells. Supplementation by implantation of NRG1-soaked beads rescued regeneration to digits in denervated limbs, and pharmacological inhibition of NRG1 signaling reduced cell proliferation, blocked blastema formation and induced aberrant collagen deposition in fully innervated limbs. Taken together, our results show that nerve-dependent NRG1\/ErbB2 signaling promotes blastemal proliferation in the regenerating limb and may play an essential role in blastema formation, thus providing insight into the longstanding question of why nerves are required for axolotl limb regeneration.<\/jats:p>","DOI":"10.1242\/dev.133363","type":"journal-article","created":{"date-parts":[[2016,6,18]],"date-time":"2016-06-18T01:58:54Z","timestamp":1466215134000},"page":"2724-2731","source":"Crossref","is-referenced-by-count":101,"title":["Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration"],"prefix":"10.1242","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6540-7870","authenticated-orcid":false,"given":"Johanna E.","family":"Farkas","sequence":"first","affiliation":[{"name":"Northeastern University 1 Department of Biology , , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina D.","family":"Freitas","sequence":"additional","affiliation":[{"name":"Northeastern University 1 Department of Biology , , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald M.","family":"Bryant","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Center and 2 \u2008 Department of Orthopedic Surgery , , Cambridge, MA 02139 , USA"},{"name":"Brigham & Women's Hospital, Harvard Medical School 2 \u2008 Department of Orthopedic Surgery , , Cambridge, MA 02139 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Whited","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Center and 2 \u2008 Department of Orthopedic Surgery , , Cambridge, MA 02139 , USA"},{"name":"Brigham & Women's Hospital, Harvard Medical School 2 \u2008 Department of Orthopedic Surgery , , Cambridge, MA 02139 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6689-6108","authenticated-orcid":false,"given":"James R.","family":"Monaghan","sequence":"additional","affiliation":[{"name":"Northeastern University 1 Department of Biology , , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2024061300012561100_DEV133363C1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.cell.2009.04.060","article-title":"Neuregulin1\/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury","volume":"138","author":"Bersell","year":"2009","journal-title":"Cell"},{"key":"2024061300012561100_DEV133363C2","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/0092-8674(86)90394-6","article-title":"Glial growth factor and nerve-dependent proliferation in the regeneration blastema of urodele amphibians","volume":"45","author":"Brockes","year":"1986","journal-title":"Cell"},{"key":"2024061300012561100_DEV133363C3","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/S0896-6273(00)80155-5","article-title":"GGF\/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors","volume":"17","author":"Canoll","year":"1996","journal-title":"Neuron"},{"key":"2024061300012561100_DEV133363C4","doi-asserted-by":"publisher","first-page":"e50265","DOI":"10.3791\/50265","article-title":"Murine model of wound healing","volume":"75","author":"Dunn","year":"2013","journal-title":"J. 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