PUBLICATION
Conserved roles for Hnf4 family transcription factors in zebrafish development and intestinal function
- Authors
- Heppert, J.K., Lickwar, C.R., Tillman, M.C., Davis, B.R., Davison, J.M., Lu, H.Y., Chen, W., Busch-Nentwich, E.M., Corcoran, D.L., Rawls, J.F.
- ID
- ZDB-PUB-221018-29
- Date
- 2022
- Source
- Genetics 222(4): (Journal)
- Registered Authors
- Busch-Nentwich, Elisabeth, Davis, Briana, Davison, James M., Heppert, Jennifer, Lickwar, Colin, Lu, Hsiu Yi "Justice", Rawls, John F., Tillman, Matthew
- Keywords
- HNF4, NR2A, host-microbe interaction, intestine, microbiota, nuclear receptor, transcription factor, zebrafish development
- Datasets
- GEO:GSE183799
- MeSH Terms
-
- Animals
- Hepatocyte Nuclear Factor 4*/genetics
- Hepatocyte Nuclear Factor 4*/physiology
- Intestinal Mucosa*/embryology
- Intestinal Mucosa*/metabolism
- Intestines/embryology
- Intestines/metabolism
- Zebrafish*/embryology
- Zebrafish*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/physiology
- PubMed
- 36218393 Full text @ Genetics
Citation
Heppert, J.K., Lickwar, C.R., Tillman, M.C., Davis, B.R., Davison, J.M., Lu, H.Y., Chen, W., Busch-Nentwich, E.M., Corcoran, D.L., Rawls, J.F. (2022) Conserved roles for Hnf4 family transcription factors in zebrafish development and intestinal function. Genetics. 222(4):.
Abstract
Transcription factors play important roles in development of the intestinal epithelium and its ability to respond to endocrine, nutritional, and microbial signals. Hepatocyte Nuclear Factor 4 (Hnf4) family nuclear receptors are liganded transcription factors that are critical for the development and function of multiple digestive organs in vertebrates, including the intestinal epithelium. Zebrafish have three Hnf4 homologs, of which, hnf4a was previously shown to mediate intestinal responses to microbiota in zebrafish larvae. To discern the functions of other Hnf4 family members in zebrafish development and intestinal function, we created and characterized mutations in hnf4g and hnf4b. We addressed the possibility of genetic redundancy amongst these factors by creating double and triple mutants which showed different rates of survival, including apparent early lethality in hnf4a;hnf4b double mutants and triple mutants. RNA sequencing performed on digestive tracts from single and double mutant larvae revealed extensive changes in intestinal gene expression in hnf4a mutants that were amplified in hnf4a;hnf4g mutants, but limited in hnf4g mutants. Changes in hnf4a and hnf4a;hnf4g mutants were reminiscent of those seen in mice including decreased expression of genes involved in intestinal function and increased expression of cell proliferation genes, and were validated using transgenic reporters and EdU labeling in the intestinal epithelium. Gnotobiotics combined with RNA sequencing also showed hnf4g has subtler roles than hnf4a in host responses to microbiota. Overall, phenotypic changes in hnf4a single mutants were strongly enhanced in hnf4a;hnf4g double mutants, suggesting a conserved partial genetic redundancy between hnf4a and hnf4g in the vertebrate intestine.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping