{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:23:03Z","timestamp":1768569783003,"version":"3.49.0"},"posted":{"date-parts":[[2025,4,3]]},"group-title":"Endocrinology (including Diabetes Mellitus and Metabolic Disease)","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The pituitary gland produces several hormones that regulate growth, metabolism, stress response, reproduction, and homeostasis. Congenital hypopituitarism is a deficiency in one or more pituitary hormones and encompasses a spectrum of clinical conditions. The pituitary has a complex embryonic origin with the oral ectoderm contributing the anterior lobe, and the neural ectoderm generating the posterior lobe. Pituitary abnormalities and growth deficiencies are associated with cleft palate however the developmental genetic connection between pituitary and orofacial cleft malformations remains to be determined. The epithelial RNA splicing regulators\n                  <jats:italic>Esrp1<\/jats:italic>\n                  and\n                  <jats:italic>Esrp2<\/jats:italic>\n                  are required for orofacial development in zebrafish, mice, and humans, and loss of function of these genes results in a cleft palate. Here we present a detailed developmental analysis of the genetic requirement for\n                  <jats:italic>Esrp1\/2<\/jats:italic>\n                  in pituitary morphogenesis in mouse and zebrafish. Further, we describe a patient with cleft palate and hypopituitarism that harbors a nucleotide variant in the RNA binding domain of\n                  <jats:italic>ESRP2<\/jats:italic>\n                  . The discovery of this key function for\n                  <jats:italic>Esrp1\/2<\/jats:italic>\n                  in pituitary formation has significant fundamental and clinical implications for understanding congenital hypopituitarism and craniofacial anomalies.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary Statement<\/jats:title>\n                  <jats:p>Esrp1 and Esrp2 are regulators of mRNA alternative splicing that are required for both orofacial and pituitary development in vertebrates.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.02.25325077","type":"posted-content","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T11:10:37Z","timestamp":1743678637000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic requirement for\n                  <i>Esrp1\/2<\/i>\n                  in vertebrate pituitary morphogenesis"],"prefix":"10.64898","author":[{"given":"Shannon H.","family":"Carroll","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sogand","family":"Schafer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariella S.","family":"Richman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Tsay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mian Umair","family":"Ahsan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5585-982X","authenticated-orcid":false,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric C.","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025040504200750000_2025.04.02.25325077v1.1","doi-asserted-by":"crossref","first-page":"696","DOI":"10.3906\/sag-1303-89","article-title":"Endocrine abnormalities of patients with cleft lip and\/or cleft palate during the neonatal period","volume":"44","year":"2014","journal-title":"Turk J Med Sci"},{"key":"2025040504200750000_2025.04.02.25325077v1.2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.161638.113"},{"key":"2025040504200750000_2025.04.02.25325077v1.3","doi-asserted-by":"crossref","unstructured":"Bebee, T.W. , Park, J.W. , Sheridan, K.I. , Warzecha, C.C. , Cieply, B.W. , Rohacek, A.M. , Xing, Y. , and Carstens, R.P . (2015). The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development. eLife 4.","DOI":"10.7554\/eLife.08954"},{"key":"2025040504200750000_2025.04.02.25325077v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/ajpa.1330750408"},{"key":"2025040504200750000_2025.04.02.25325077v1.5","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1038\/s41467-017-01961-y","article-title":"Evolutionary recruitment of flexible Esrp-dependent splicing programs into diverse embryonic morphogenetic processes","volume":"8","year":"2017","journal-title":"Nature communications"},{"key":"2025040504200750000_2025.04.02.25325077v1.6","doi-asserted-by":"crossref","unstructured":"Caetano da Silva , C., Macias Trevino , C., Mitchell , J., Murali , H., Tsimbal , C., Dalessandro , E., Carroll , S.H., Kochhar , S., Curtis , S.W., Cheng , C.H.E., et al. (2024). Functional analysis of ESRP1\/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis. Commun Biol 7, 1040.","DOI":"10.1038\/s42003-024-06715-3"},{"key":"2025040504200750000_2025.04.02.25325077v1.7","doi-asserted-by":"crossref","unstructured":"Camper, S.A. , Smith, C. , and Kitzman, J.O . (2023). Disruption of RNA Splicing Is an Important Contributor to Congenital Hypopituitarism and Other Human Genetic Diseases. Endocrinology 164.","DOI":"10.1210\/endocr\/bqad039"},{"key":"2025040504200750000_2025.04.02.25325077v1.8","doi-asserted-by":"crossref","unstructured":"Carroll, S.H. , Macias Trevino, C. , Li, E.B. , Kawasaki, K. , Myers, N. , Hallett, S.A. , Alhazmi, N. , Cotney, J. , Carstens, R.P. , and Liao, E.C . (2020). An Irf6-Esrp1\/2 regulatory axis controls midface morphogenesis in vertebrates. 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(2020). The Molecular Basis of Congenital Hypopituitarism and Related Disorders. 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