IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas.
Neurogenin 3 (Ngn3) is key for endocrine cell specification in the embryonic pancreas and induction of a neuroendocrine cell differentiation program by misexpression in adult pancreatic duct cells. We identify the gene encoding IA1, a zinc-finger transcription factor, as a direct target of Ngn3 and show that it forms a novel branch in the Ngn3-dependent endocrinogenic transcription factor network. During embryonic development of the pancreas, IA1 and Ngn3 exhibit nearly identical spatio-temporal expression patterns. However, embryos lacking Ngn3 fail to express IA1 in the pancreas. Upon ectopic expression in adult pancreatic duct cells Ngn3 binds to chromatin in the IA1 promoter region and activates transcription. Consistent with this direct effect, IA1 expression is normal in embryos mutant for NeuroD1, Arx, Pax4 and Pax6, regulators operating downstream of Ngn3. IA1 is an effector of Ngn3 function as inhibition of IA1 expression in embryonic pancreas decreases the formation of insulin- and glucagon-positive cells by 40%, while its ectopic expression amplifies neuroendocrine cell differentiation by Ngn3 in adult duct cells. IA1 is therefore a novel Ngn3-regulated factor required for normal differentiation of pancreatic endocrine cells.
Mellitzer
Georg
G
Inserm' U682, Development and Physiopathology of the Intestine and Pancreas, Université Louis Pasteur, Strasbourg, France.
Bonné
Stefan
S
Luco
Reini F
RF
Van De Casteele
Mark
M
Lenne-Samuel
Nathalie
N
Collombat
Patrick
P
Mansouri
Ahmed
A
Lee
Jacqueline
J
Lan
Michael
M
Pipeleers
Daniel
D
Nielsen
Finn C
FC
Ferrer
Jorge
J
Gradwohl
Gérard
G
Heimberg
Harry
H
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005934:Glucagon / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016335:Zinc Fingers
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D005934:Glucagon; D018398:Homeodomain Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C469265:ARX protein, mouse; C501008:Neurod1 protein, mouse; C407737:Neurog3 protein, mouse; C000605730:PAX6 protein, human; C110218:Pax4 protein, mouse; C000605732:Pax6 protein, mouse; C087342:INSM1 protein, human