PDX:PBX complexes are required for normal proliferation of pancreatic cells during development.
The homeobox factor PDX-1 is a key regulator of pancreatic morphogenesis and glucose homeostasis; targeted disruption of the PDX-1 gene leads to pancreatic agenesis in pdx-1(-/-) homozygotes. Pdx-1 heterozygotes develop normally, but they display glucose intolerance in adulthood. Like certain other homeobox proteins, PDX-1 contains a consensus FPWMK motif that promotes heterodimer formation with the ubiquitous homeodomain protein PBX. To evaluate the importance of PDX-1:PBX complexes in pancreatic morphogenesis and glucose homeostasis, we expressed either wild-type or PBX interaction defective PDX-1 transgenes under control of the PDX-1 promoter. Both wild-type and mutant PDX-1 transgenes corrected glucose intolerance in pdx-1 heterozygotes. The wild-type PDX-1 transgene rescued the development of all pancreatic lineages in pdx-1(-/-) animals, and these mice survived to adulthood. In contrast, pancreata from pdx-1(-/-) mice expressing the mutant PDX-1 transgene were hypoplastic, and these mice died within 3 weeks of birth from pancreatic insufficiency. All pancreatic cell types were observed in pdx-1(-/-) mice expressing the mutant PDX-1 transgene; but the islets were smaller, and increased numbers of islet hormone-positive cells were noted within the ductal epithelium. These results indicate that PDX-1:PBX complexes are dispensable for glucose homeostasis and for differentiation of stem cells into ductal, endocrine, and acinar lineages; but they are essential for expansion of these populations during development.
Dutta
S
S
Clayton Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Gannon
M
M
Peers
B
B
Wright
C
C
Bonner-Weir
S
S
Montminy
M
M
D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology*; D003643:Death; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006706:Homeostasis; D007515:Islets of Langerhans / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D016297:Mutagenesis, Site-Directed; D010179:Pancreas / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D010183:Pancreatic Ducts / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C083400:PBX1 protein, human; D005947:Glucose