TY - JOUR
T1 - Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism
AU - Jørgensen, Mette Christine
AU - Ahnfelt-Rønne, Jonas
AU - Klinck, Rasmus
AU - Jensen, Jan N
AU - Füchtbauer, Ernst-Martin
AU - Deering, Tye
AU - MacDonald, Raymond J
AU - Wright, Chris V E
AU - Madsen, Ole D
AU - Serup, Palle
PY - 2011
Y1 - 2011
N2 - Neurog3-induced Dll1 expression in pancreatic endocrine progenitors ostensibly activates Hes1 expression via Notch and thereby represses Neurog3 and endocrine differentiation in neighboring cells by lateral inhibition. Here we show in mouse that Dll1 and Hes1 expression deviate during regionalization of early endoderm, and later during early pancreas morphogenesis. At that time, Ptf1a activates Dll1 in multipotent pancreatic progenitor cells (MPCs), and Hes1 expression becomes Dll1 dependent over a brief time window. Moreover, Dll1, Hes1 and Dll1/Hes1 mutant phenotypes diverge during organ regionalization, become congruent at early bud stages, and then diverge again at late bud stages. Persistent pancreatic hypoplasia in Dll1 mutants after eliminating Neurog3 expression and endocrine development, together with reduced proliferation of MPCs in both Dll1 and Hes1 mutants, reveals that the hypoplasia is caused by a growth defect rather than by progenitor depletion. Unexpectedly, we find that Hes1 is required to sustain Ptf1a expression, and in turn Dll1 expression in early MPCs. Our results show that Ptf1a-induced Dll1 expression stimulates MPC proliferation and pancreatic growth by maintaining Hes1 expression and Ptf1a protein levels.
AB - Neurog3-induced Dll1 expression in pancreatic endocrine progenitors ostensibly activates Hes1 expression via Notch and thereby represses Neurog3 and endocrine differentiation in neighboring cells by lateral inhibition. Here we show in mouse that Dll1 and Hes1 expression deviate during regionalization of early endoderm, and later during early pancreas morphogenesis. At that time, Ptf1a activates Dll1 in multipotent pancreatic progenitor cells (MPCs), and Hes1 expression becomes Dll1 dependent over a brief time window. Moreover, Dll1, Hes1 and Dll1/Hes1 mutant phenotypes diverge during organ regionalization, become congruent at early bud stages, and then diverge again at late bud stages. Persistent pancreatic hypoplasia in Dll1 mutants after eliminating Neurog3 expression and endocrine development, together with reduced proliferation of MPCs in both Dll1 and Hes1 mutants, reveals that the hypoplasia is caused by a growth defect rather than by progenitor depletion. Unexpectedly, we find that Hes1 is required to sustain Ptf1a expression, and in turn Dll1 expression in early MPCs. Our results show that Ptf1a-induced Dll1 expression stimulates MPC proliferation and pancreatic growth by maintaining Hes1 expression and Ptf1a protein levels.
KW - Animals
KW - Basic Helix-Loop-Helix Transcription Factors
KW - Bromodeoxyuridine
KW - Chromatin Immunoprecipitation
KW - Galactosides
KW - Gene Expression Regulation
KW - Homeodomain Proteins
KW - Immunohistochemistry
KW - Indoles
KW - Intercellular Signaling Peptides and Proteins
KW - Mice
KW - Mice, Transgenic
KW - Nerve Tissue Proteins
KW - Pancreas
KW - Pancreatic Polypeptide-Secreting Cells
KW - Stem Cells
KW - Transcription Factors
U2 - 10.1242/dev.071761
DO - 10.1242/dev.071761
M3 - Journal article
C2 - 22096075
SN - 0950-1991
VL - 139
SP - 33
EP - 45
JO - Development
JF - Development
IS - 1
ER -