Intestinal Neurogenin 3 directs differentiation of a bipotential secretory progenitor to endocrine cell rather than goblet cell fate

Lopez-Diaz, Lymari; Jain, Renu; Keeley, Theresa M.; VanDussen, Kelli L.; Brunkan, Cynthia S.; Gumucio, Deborah L.; Samuelson, Linda C.

doi:10.1016/j.ydbio.2007.07.015

Cited by 71 publications

(53 citation statements)

References 28 publications

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“…In the mouse embryo, the development of enteroendocrine cells relies on the proendocrine transcription factor neurogenin 3, which promotes the endocrine fate in pluripotent intestinal stem cells (12,13,15). Indeed, in Ngn3-deficient mice, neither enteroendocrine nor pancreatic endocrine cells develop, and the mice die postnatally due to severe diabetes (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Neurogenin 3 (Ngn3) has been shown to be the key gene controlling the commitment of pluripotent progenitor cells toward the endocrine cell lineage in the developing pancreas (11) and intestine (12,13). Ngn3-deficient mice do not develop any enteroendocrine and pancreatic endocrine cells, and mice show severe diabetes and die shortly after birth (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival

Mellitzer¹,

Beucher²,

Lobstein³

et al. 2010

J. Clin. Invest.

102

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At least 10 enteroendocrine cell types have been identified, and the peptide hormones they secrete have diverse functions that include regulation of glucose homeostasis, food intake, and gastric emptying. Mice lacking individual enteroendocrine hormones, their receptors, or combinations of these have shed light on the role of these hormones in the regulation of energy homeostasis. However, because enteroendocrine hormones have partially overlapping functions, these loss-of-function studies produced only minor phenotypes, and none of the enteroendocrine hormones was shown to be essential for life. To examine the effect of loss of all enteroendocrine cells and hormones on energy homeostasis, we generated mice with intestinal-specific ablation of the proendocrine transcription factor neurogenin 3 (referred to herein as Ngn3 Δint mice). Ngn3 Δint mice were deficient for all enteroendocrine cells and hormones, and died with a high frequency during the first week of life. Mutant mice were growth retarded and had yellowish stool suggestive of steatorrhea. Subsequent analyses revealed that Ngn3 Δint mice had impaired lipid absorption, reduced weight gain, and improved glucose homeostasis. Furthermore, intestinal epithelium of the mutant mice showed an enlarged proliferative crypt compartment and accelerated cell turnover but no changes to goblet and Paneth cell numbers. Enterocytes had shorter microvilli, but the expression of the main brush border enzymes was unaffected. Our data help unravel the role of enteroendocrine cells and hormones in lipid absorption and maintenance of the intestinal epithelium.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival

Mellitzer¹,

Beucher²,

Lobstein³

et al. 2010

J. Clin. Invest.

102

View full text Add to dashboard Cite

show abstract

“…The expression level of genes encoding the gut hormones glucose-dependent insulinotropic peptide, somatostatin, and glucagon was significantly decreased ( Table 2), suggesting that the corresponding endocrine subtypes were reduced. The transcription factors Ngn-3 and NeuroD were reported to be involved in enteroendocrine specification and differentiation (31). The mRNA encoding Ngn-3 was significantly increased in Hnf-4a int⌬ mice, whereas that encoding NeuroD remained unchanged (Table 2).…”

Section: Loss Of Hnf-4␣ Enhances the Proliferation Of Epithelial Cellmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium

Cattin

Beyec

Barreau

et al. 2009

Molecular and Cellular Biology

137

129

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Hepatocyte nuclear factor 4␣ (HNF-4␣) is a transcription factor which is highly expressed in the intestinal epithelium from duodenum to colon and from crypt to villus. The homeostasis of this constantly renewing epithelium relies on an integrated control of proliferation, differentiation, and apoptosis, as well as on the functional architecture of the epithelial cells. In order to determine the consequences of HNF-4␣ loss in the adult intestinal epithelium, we used a tamoxifen-inducible Cre-loxP system to inactivate the Hnf-4a gene. In the intestines of adult mice, loss of HNF-4␣ led to an increased proliferation in crypts and to an increased expression of several genes controlled by the Wnt/␤-catenin system. This control of the Wnt/␤-catenin signaling pathway by HNF-4␣ was confirmed in vitro. Cell lineage was affected, as indicated by an increased number of goblet cells and an impairment of enterocyte and enteroendocrine cell maturation. In the absence of HNF-4␣, cell-cell junctions were destabilized and paracellular intestinal permeability increased. Our results showed that HNF-4␣ modulates Wnt/␤-catenin signaling and controls intestinal epithelium homeostasis, cell function, and cell architecture. This study indicates that HNF-4␣ regulates the intestinal balance between proliferation and differentiation, and we hypothesize that it might act as a tumor suppressor.

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“…The basic helix-loop-helix (bHLH) protein neurogenin 3 (Ngn3, or Neurog3) is expressed in enteroendocrine progenitor cells and is required for induction of the enteroendocrine cell lineage (Jenny et al, 2002;Lopez-Diaz et al, 2007;Schonhoff et al, 2004). Ngn3 −/− mice do not develop enteroendocrine cells in the intestinal epithelium (Jenny et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

et al. 2016

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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.

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Intestinal Neurogenin 3 directs differentiation of a bipotential secretory progenitor to endocrine cell rather than goblet cell fate

Cited by 71 publications

References 28 publications

Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival

Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival

Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

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