Stomach Organ and Cell Lineage Differentiation: From Embryogenesis to Adult Homeostasis

Willet, Spencer G.; Mills, Jason C.

doi:10.1016/j.jcmgh.2016.05.006

Cited by 90 publications

(111 citation statements)

References 125 publications

(159 reference statements)

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…The Notch signaling pathway is critical for gastrointestinal cell fate determination 5, 55, 56. In the adult intestines, activation of Notch signaling induces the expression of HES1, which directly represses Atoh1 , and thus directs progenitors to differentiate along the absorptive lineage.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine

Chung

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

View full text Add to dashboard Cite

Background & AimsThe transcription factor atonal homolog 1 (ATOH1) controls the fate of intestinal progenitors downstream of the Notch signaling pathway. Intestinal progenitors that escape Notch activation express high levels of ATOH1 and commit to a secretory lineage fate, implicating ATOH1 as a gatekeeper for differentiation of intestinal epithelial cells. Although some transcription factors downstream of ATOH1, such as SPDEF, have been identified to specify differentiation and maturation of specific cell types, the bona fide transcriptional targets of ATOH1 still largely are unknown. Here, we aimed to identify ATOH1 targets and to identify transcription factors that are likely to co-regulate gene expression with ATOH1.MethodsWe used a combination of chromatin immunoprecipitation and messenger RNA–based high-throughput sequencing (ChIP-seq and RNA-seq), together with cell sorting and transgenic mice, to identify direct targets of ATOH1, and establish the epistatic relationship between ATOH1 and SPDEF.ResultsBy using unbiased genome-wide approaches, we identified more than 700 genes as ATOH1 transcriptional targets in adult small intestine and colon. Ontology analysis indicated that ATOH1 directly regulates genes involved in specification and function of secretory cells. De novo motif analysis of ATOH1 targets identified SPDEF as a putative transcriptional co-regulator of ATOH1. Functional epistasis experiments in transgenic mice show that SPDEF amplifies ATOH1-dependent transcription but cannot independently initiate transcription of ATOH1 target genes.ConclusionsThis study unveils the direct targets of ATOH1 in the adult intestines and illuminates the transcriptional events that initiate the specification and function of intestinal secretory lineages.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine

Chung

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

View full text Add to dashboard Cite

show abstract

“…The XBP1 → MIST1 cassette is required in secretory cells of diverse tissues to establish the cargogenerating, packaging, and secreting machinery for professional secretory cells (Metzler et al 2015). The epithelium of the body of the stomach is a good model for studying cell fate-determining transcription factors versus scaling factors because it is organized into roughly tubular invaginations (units) with distinct zones of cell types and a stem cell that actively generates all of the cell types throughout life (Mills and Shivdasani 2011;Willet and Mills 2016). The two key long-lived cell types in the gastric unit are the acid-pumping parietal cells (PCs) and the digestive enzyme-secreting zymogenic chief cells (ZCs).…”

mentioning

confidence: 99%

A single transcription factor is sufficient to induce and maintain secretory cell architecture

Jin

Sibbel

et al. 2017

Genes Dev.

Self Cite

View full text Add to dashboard Cite

We hypothesized that basic helix-loop-helix (bHLH) MIST1 (BHLHA15) is a "scaling factor" that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules. Mist1 induced a cohort of genes regulated by MIST1 in multiple organs but did not affect PC function. MIST1 bound CATATG/CAGCTG E boxes in the first intron of genes that regulate autophagosome/lysosomal degradation, mitochondrial trafficking, and amino acid metabolism. Similar alterations in cell architecture and gene expression were also caused by ectopically inducing MIST1 in vivo in hepatocytes. Thus, MIST1 is a scaling factor necessary and sufficient by itself to induce and maintain secretory cell architecture. Our results indicate that, whereas mature cell types in each organ may have unique developmental origins, cells performing similar physiological functions throughout the body share similar transcription factor-mediated architectural "blueprints."

show abstract

“…Since KO mice depleted of mature chief cells still develop SPEM, mature chief cells may not be the origin of SPEM in the current mouse model. Expressions of Xbp1 and Mist1 (gene Bhlha15) were low in KO mice and these are important for chief cells to form zymogen-containing vesicles [53,54]. In the current mouse model, one could speculate that SPEM develops from the large proportion of cells previously described as immature cells in young KO mice [50], possibly represented chief cells devoid of granules.…”

Section: Discussionmentioning

confidence: 67%

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice

Aasarød

Stunes

Sandvik

et al. 2020

IJMS

View full text Add to dashboard Cite

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

show abstract

Stomach Organ and Cell Lineage Differentiation: From Embryogenesis to Adult Homeostasis

Cited by 90 publications

References 125 publications

Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine

Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine

A single transcription factor is sufficient to induce and maintain secretory cell architecture

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice

Contact Info

Product

Resources

About