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To test the hypothesis that\n                    <jats:italic>DLK1<\/jats:italic>\n                    plays a role in gonadotropin releasing hormone (GnRH) neuron ontogeny, 75 base pairs were deleted in both alleles of\n                    <jats:italic>DLK1<\/jats:italic>\n                    exon 3 with CRISPR-Cas9 in human pluripotent stem cells (hPSCs). This line, exhibiting More than 80% loss of DLK1 protein, was differentiated into GnRH neurons by dual SMAD inhibition (dSMADi), FGF8 treatment and Notch inhibition, as previously described, however, it did not exhibit accelerated\n                    <jats:italic>GNRH1<\/jats:italic>\n                    expression. Activation of (WT)\n                    <jats:italic>DLK1<\/jats:italic>\n                    with CRISPRa during dSMADi suppressed the formation of anterior neuronal precursors, and almost completely inhibited GnRH neuron fate. Instead, it induced the expression of Wnt pathway genes, markers of proliferating and non-proliferating neuronal progenitors, and dorsal spinal cord interneurons. Activation of\n                    <jats:italic>DLK1<\/jats:italic>\n                    expression, during the FGF8 phase, significantly increased\n                    <jats:italic>GNRH1<\/jats:italic>\n                    expression and secretion of GnRH decapeptide. In conclusion, significant loss of DLK1 protein did not accelerate\n                    <jats:italic>GNRH1<\/jats:italic>\n                    expression, suggesting that CPP caused by paternally inherited loss-of-function mutations is due to mechanisms acting up- or downstream of GnRH neurons. Conversely, timing of\n                    <jats:italic>DLK1<\/jats:italic>\n                    activation emerged as an important factor in determining GnRH neuron fate, with early expression disrupting GnRH lineage commitment and later activation enhancing\n                    <jats:italic>GNRH1<\/jats:italic>\n                    expression.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s12015-025-10972-y","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T10:14:10Z","timestamp":1757412850000},"page":"2711-2726","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Role of DLK1 in GnRH Neuron Ontogeny"],"prefix":"10.1007","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0460-0700","authenticated-orcid":false,"given":"Nazli","family":"Eskici","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celia","family":"Gomez-Sanchez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shrinidhi","family":"Madhusudan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristiina","family":"Pulli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salla","family":"Keskitalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Turunen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsi","family":"Vaaralahti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yafei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markku","family":"Varjosalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taneli","family":"Raivio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"issue":"1","key":"10972_CR1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/ng1233","volume":"35","author":"SP Lin","year":"2003","unstructured":"Lin, S. 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