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Reduction of Ptf1a Gene Dosage Causes Pancreatic Hypoplasia and Diabetes in Mice
Akihisa Fukuda 1 2 3 ,
Yoshiya Kawaguchi 1 ,
Kenichiro Furuyama 1 ,
Sota Kodama 1 ,
Masashi Horiguchi 1 ,
Takeshi Kuhara 1 ,
Michiya Kawaguchi 1 ,
Mami Terao 4 ,
Ryuichiro Doi 1 ,
Christopher V.E. Wright 5 ,
Mikio Hoshino 4 6 ,
Tsutomu Chiba 2 and
Shinji Uemoto 1
1 Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
2 Department of Gastroenterology & Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
3 Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California
4 Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan
5 Vanderbilt Developmental Biology Program, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine,
Nashville, Tennessee
6 Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry,
Tokyo, Japan
Corresponding author: Yoshiya Kawaguchi, yoshiyak{at}kuhp.kyoto-u.ac.jp
Abstract
OBJECTIVE— Most 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.
RESEARCH DESIGN AND METHODS— Combining 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.
RESULTS— Reduced 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 β-cell number was decreased, proportion of non-β islet cells was increased, and α-cells were
abnormally intermingled with β-cells. Interestingly, Pdx1 expression was decreased in early pancreatic progenitors but elevated to normal level at the mid-to-late stages of pancreatogenesis.
CONCLUSIONS— The dosage of Ptf1a is crucial for pancreas specification, growth, total β-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.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 30 June 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted June 11, 2008.
Received November 2, 2007.
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