Cell Lineage metastability in Gfi1-deficient mouse intestinal epithelium.
Elucidating the mechanisms determining multipotent progenitor cell fate remains a fundamental project of contemporary biology. Various tissues of mice and men with defects in the zinc-finger transcriptional repressor Gfi1 have dramatic perturbations in the proportions of their differentiated cell types. In Gfi1-deficient intestinal epithelium there is a shift from mucous and Paneth towards enteroendocrine cells, leading to the proposal that Gfi1 functions in the allocation of the progeny derived from a hypothetical common granulocytic progenitor. However, studies of clones have yielded no evidence of such a common progenitor prompting us to investigate alternate mechanisms explaining the Gfi1-deficient phenotype. We report that mucous and Paneth but not enteroendocrine lineage cells normally express Gfi1. Sporadic mucous and Paneth lineage cells in the crypts of Gfi1-deficient mice aberrantly express the pro-enteroendocrine transcription factor Neurog3, indicating that stable repression of Neurog3 in these lineages requires Gfi1. Importantly, we also find mucous and Paneth lineage cells in various stages of cellular reprogramming into the enteroendocrine lineage in Gfi1-deficient mice. We propose that mucous and Paneth cell lineage metastability, rather than reallocation at the level of a hypothetical common granulocytic progenitor, is responsible for the shifts in cell type proportions observed in Gfi1-deficient intestinal epithelium.
Bjerknes
Matthew
M
Department of Medicine, Clinical Science Division, Medical Sciences Building, Room 6334, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. matthew.bjerknes@utoronto.ca
Cheng
Hazel
H
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D005434:Flow Cytometry; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019879:Paneth Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C079873:Gfi1 protein, mouse; C407737:Neurog3 protein, mouse