Genetic identification of a novel NeuroD1 function in the early differentiation of islet alpha, PP and epsilon cells.
Nkx2.2 and NeuroD1 are vital for proper differentiation of pancreatic islet cell types. Nkx2.2-null mice fail to form beta cells, have reduced numbers of alpha and PP cells and display an increase in ghrelin-producing epsilon cells. NeuroD1-null mice display a reduction of alpha and beta cells after embryonic day (e) 17.5. To begin to determine the relative contributions of Nkx2.2 and NeuroD1 in islet development, we generated Nkx2.2-/-;NeuroD1-/- double knockout (DKO) mice. As expected, the DKO mice fail to form beta cells, similar to the Nkx2.2-null mice, suggesting that the Nkx2.2 phenotype may be dominant over the NeuroD1 phenotype in the beta cells. Surprisingly, however, the alpha, PP and epsilon phenotypes of the Nkx2.2-null mice are partially rescued by the simultaneous elimination of NeuroD1, even at early developmental time points when NeuroD1 null mice alone do not display a phenotype. Our results indicate that Nkx2.2 and NeuroD1 interact to regulate pancreatic islet cell fates, and this epistatic relationship is cell-type dependent. Furthermore, this study reveals a previously unappreciated early function of NeuroD1 in regulating the specification of alpha, PP and epsilon cells.
Chao
Christina S
CS
University of Colorado at Denver and Health Science Center, Biochemistry and Molecular Genetics Department, Aurora, CO 80045, USA.
Loomis
Zoe L
ZL
Lee
Jacqueline E
JE
Sussel
Lori
L
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D054439:Ghrelin / Q000096:biosynthesis; D005934:Glucagon / Q000096:biosynthesis; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050809:POU Domain Factors / Q000378:metabolism; D050418:Pancreatic Polypeptide-Secreting Cells / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D054439:Ghrelin; D005934:Glucagon; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D012333:RNA, Messenger; D014157:Transcription Factors; D029961:Zebrafish Proteins; C501008:Neurod1 protein, mouse; C000715627:Nkx2-2 protein, mouse; C000715630:nkx2.2b protein, zebrafish; C074067:Pou3f4 protein, mouse