Small intestinal villi are structural and functional units present in higher vertebrates and uniquely adapted to nutrient absorption. Villus enterocytes are organized in transcriptional “zones” dedicated to specialized tasks such as absorption of specific nutrients. We report that the transcription factor c-MAF is expressed in differentiated lower and mid-villus enterocytes and is a target of BMP signaling. Maf inactivation perturbed the villus zonation program by increasing carbohydrate-related transcripts while suppressing transcripts linked to amino-acid and lipid absorption. The formation of cytoplasmic lipid droplets, shuttling dietary fat to chylomicrons, was impaired upon Maf loss indicating its role in dietary lipid handling. Maf inactivation under homeostatic conditions expanded tuft cells and led to compensatory gut lengthening, preventing weight loss. However, delayed Maf−/− enterocyte maturation impaired weight recovery after acute intestinal injury, resulting in reduced survival. Our results identify c-MAF as a regulator of the intestinal villus zonation program, while highlighting the importance of coordination between stem/progenitor and differentiation programs for intestinal regeneration.
c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs
Disclosures: The Ecole Polytechnique Fédérale de Lausanne has filed for patent protection (EP16199677.2, PCT/EP2017/079651, US20190367872A1) on the scaffold-guided organoid technology, where M.P. Lutolf is named as inventor. M.P. Lutolf is a shareholder in SUN bioscience SA, which is commercializing those patents. No other disclosures were reported.
A. González-Loyola’s present address is Biomechanical Engineering Department, University of Zaragoza, Zaragoza, Spain.
O. Munoz’s present address is Services of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Epalinges, Switzerland.
B. Prat-Luri’s present address is Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
- Award Id(s): CRSII5_177191,31ER30_160674,31003A-156266,CRSK-3_190200
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Alejandra González-Loyola, Jeremiah Bernier-Latmani, Irena Roci, Tania Wyss, Jakob Langer, Stephan Durot, Olivia Munoz, Borja Prat-Luri, Mauro Delorenzi, Matthias P. Lutolf, Nicola Zamboni, Grégory Verdeil, Tatiana V. Petrova; c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs. J Exp Med 5 December 2022; 219 (12): e20212418. doi: https://doi.org/10.1084/jem.20212418
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