{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:32:35Z","timestamp":1791181955501,"version":"4.1.0"},"reference-count":29,"publisher":"American Diabetes Association","issue":"9","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,9,1]]},"abstract":"<jats:p>OBJECTIVE\u2014Most pancreatic endocrine cells derive from Ptf1a-expressing progenitor cells. In humans, nonsense mutations in Ptf1a have recently been identified as a cause of permanent neonatal diabetes associated with pancreatic agenesis. The death of Ptf1a-null mice soon after birth has not allowed further insight into the pathogenesis of the disease; it is therefore unclear how much pancreatic endocrine function is dependent on Ptf1a in mammals. This study aims to investigate gene-dosage effects of Ptf1a on pancreas development and function in mice.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014Combining hypomorphic and null alleles of Ptf1a and Cre-mediated lineage tracing, we followed the cell fate of reduced Ptf1a-expressing progenitors and analyzed pancreas development and function in mice.<\/jats:p>\n               <jats:p>RESULTS\u2014Reduced Ptf1a dosage resulted in pancreatic hypoplasia and glucose intolerance with insufficient insulin secretion in a dosage-dependent manner. In hypomorphic mutant mice, pancreatic bud size was small and substantial proportions of pancreatic progenitors were misspecified to the common bile duct and duodenal cells. Growth with branching morphogenesis and subsequent exocrine cytodifferentiation was reduced and delayed. Total \u03b2-cell number was decreased, proportion of non-\u03b2 islet cells was increased, and \u03b1-cells were abnormally intermingled with \u03b2-cells. Interestingly, Pdx1 expression was decreased in early pancreatic progenitors but elevated to normal level at the mid-to-late stages of pancreatogenesis.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014The dosage of Ptf1a is crucial for pancreas specification, growth, total \u03b2-cell number, islet morphogenesis, and endocrine function. Some neonatal diabetes may be caused by mutation or single nucleotide polymorphisms in the Ptf1a gene that reduce gene expression levels.<\/jats:p>","DOI":"10.2337\/db07-1558","type":"journal-article","created":{"date-parts":[[2008,7,1]],"date-time":"2008-07-01T00:45:07Z","timestamp":1214873107000},"page":"2421-2431","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":66,"title":["Reduction of <i>Ptf1a<\/i> Gene Dosage Causes Pancreatic Hypoplasia and Diabetes in Mice"],"prefix":"10.2337","volume":"57","author":[{"given":"Akihisa","family":"Fukuda","sequence":"first","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"},{"name":"Department of Gastroenterology & Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan"},{"name":"Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiya","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Furuyama","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sota","family":"Kodama","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Horiguchi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kuhara","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiya","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mami","family":"Terao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichiro","family":"Doi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher V.E.","family":"Wright","sequence":"additional","affiliation":[{"name":"Vanderbilt Developmental Biology Program, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikio","family":"Hoshino","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan"},{"name":"Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Chiba","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology & Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Uemoto","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031210114394200_R1","doi-asserted-by":"crossref","unstructured":"Vivian JL, Gan L, Olson EN, Klein WH: A hypomorphic myogenin allele reveals distinct myogenin expression levels required for viability, skeletal muscle development, and sternum formation. 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