The homeodomain protein PDX1 is required at mid-pancreatic development for the formation of the exocrine pancreas.
The homeoprotein PDX1 is expressed throughout pancreatic development and is thought to play important roles at multiple stages. We describe the properties of a tet-off regulatory scheme to manage the expression of Pdx1 in utero. Cessation of Pdx1 expression at increasingly later gestational times blocked pancreatic development at progressive and morphologically distinct stages and provided the opportunity to assess the requirement for Pdx1 at each stage. Embryonic PDX1 is depleted below effective levels within 1 day of the initiation of doxycycline treatment of pregnant mice. We show that PDX1, which is necessary for early pancreatic development, is also required later for the genesis of acinar tissue, the compartment of the pancreas that produces digestive enzymes. Without PDX1, acini do not form; the precursor epithelium continues to grow and branch, creating a truncated ductal tree comprising immature duct-like cells. The bHLH factor PTF1a, a critical regulator of acinar development, is not expressed and cells producing digestive enzymes are rare. This approach should be generally applicable to study the in vivo functions of other developmental regulators with multiple, temporally distinct roles.
Hale
Michael A
MA
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148, USA.
Kagami
Hideaki
H
Shi
Ling
L
Holland
Andrew M
AM
Elsässer
Hans-Peter
HP
Hammer
Robert E
RE
MacDonald
Raymond J
RJ
D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D005865:Gestational Age; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D011247:Pregnancy; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004318:Doxycycline