A single transcription factor is sufficient to induce and maintain secretory cell architecture.
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.Mist1induced 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."
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Hei-Yong G
HG
Lo
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ramon U
RU
Jin
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Greg
G
Sibbel
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Dengqun
D
Liu
Department of Biological Sciences, The Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47906, USA.|the Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47906, USA.
Anju
A
Karki
Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Matthew S
MS
Joens
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Blair B
BB
Madison
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Bo
B
Zhang
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Valerie
V
Blanc
Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
James A J
JA
Fitzpatrick
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Nicholas O
NO
Davidson
Department of Biological Sciences, The Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47906, USA.|the Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47906, USA.
Stephen F
SF
Konieczny
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Jason C
JC
Mills
D061354:Acinar Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002460:Cell Line; D000066630:Ectopic Gene Expression / Q000187:drug effects; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D010295:Parietal Cells, Gastric / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D055571:Secretory Pathway / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D013629:Tamoxifen; D017228:Hepatocyte Growth Factor
5330417C22Rik; FIB-SEM; RAB26; UFM1; acid secretion