The novel enterochromaffin marker Lmx1a regulates serotonin biosynthesis in enteroendocrine cell lineages downstream of Nkx2.2.
Intestinal hormone-producing cells represent the largest endocrine system in the body, but remarkably little is known about enteroendocrine cell type specification in the embryo and adult. We analyzed stage- and cell type-specific deletions of Nkx2.2 and its functional domains in order to characterize its role in the development and maintenance of enteroendocrine cell lineages in the mouse duodenum and colon. Although Nkx2.2 regulates enteroendocrine cell specification in the duodenum at all stages examined, it controls the differentiation of progressively fewer enteroendocrine cell populations when deleted from Ngn3(+) progenitor cells or in the adult duodenum. During embryonic development Nkx2.2 regulates all enteroendocrine cell types, except gastrin and preproglucagon. In developing Ngn3(+) enteroendocrine progenitor cells, Nkx2.2 is not required for the specification of neuropeptide Y and vasoactive intestinal polypeptide, indicating that a subset of these cell populations derive from an Nkx2.2-independent lineage. In adult duodenum, Nkx2.2 becomes dispensable for cholecystokinin and secretin production. In all stages and Nkx2.2 mutant conditions, serotonin-producing enterochromaffin cells were the most severely reduced enteroendocrine lineage in the duodenum and colon. We determined that the transcription factor Lmx1a is expressed in enterochromaffin cells and functions downstream of Nkx2.2. Lmx1a-deficient mice have reduced expression of Tph1, the rate-limiting enzyme for serotonin biosynthesis. These data clarify the function of Nkx2.2 in the specification and homeostatic maintenance of enteroendocrine populations, and identify Lmx1a as a novel enterochromaffin cell marker that is also essential for the production of the serotonin biosynthetic enzyme Tph1.
Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA.
Stefanie
0000-0002-5259-458X
S
Gross
Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA.
Diana C
DC
Garofalo
Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA.
Dina A
DA
Balderes
Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA.
Teresa L
TL
Mastracci
Department of Cell and Molecular Biology, Karolinska Institute, von Eulers v. 3, 171 77, Stockholm, Sweden.
José M
JM
Dias
Department of Cell and Molecular Biology, Karolinska Institute, von Eulers v. 3, 171 77, Stockholm, Sweden Ludwig Institute for Cancer Research, Stockholm Branch, Nobels v. 3, 171 77, Stockholm, Sweden.
Thomas
T
Perlmann
Department of Cell and Molecular Biology, Karolinska Institute, von Eulers v. 3, 171 77, Stockholm, Sweden.
Johan
0000-0003-0135-3871
J
Ericson
Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA lori.sussel@ucdenver.edu.
Lori
0000-0003-2832-1319
L
Sussel
D000375:Aging / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics; D003106:Colon / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D004759:Enterochromaffin Cells / Q000166:cytology*; D019858:Enteroendocrine Cells / Q000166:cytology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D000072417:Protein Domains; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D012701:Serotonin / Q000096:biosynthesis*; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D029961:Zebrafish Proteins
D015415:Biomarkers; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C489692:Lmx1a protein, mouse; C000715627:Nkx2-2 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D012701:Serotonin
Enterochromaffin; Enteroendocrine cells; Intestine; Lmx1a; Nkx2.2; Serotonin