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Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9290-E9299. doi: 10.1073/pnas.1712511114. Epub 2017 Oct 17.

Control of growth and gut maturation by HoxD genes and the associated lncRNA Haglr.

Author information

1
Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland.
2
School of Life Sciences, Federal Institute of Technology, Lausanne (EPFL), 1015 Lausanne, Switzerland.
3
Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland; Denis.Duboule@epfl.ch.

Abstract

During embryonic development, Hox genes participate in the building of a functional digestive system in metazoans, and genetic conditions involving these genes lead to important, sometimes lethal, growth retardation. Recently, this phenotype was obtained after deletion of Haglr, the Hoxd antisense growth-associated long noncoding RNA (lncRNA) located between Hoxd1 and Hoxd3 In this study, we have analyzed the function of Hoxd genes in delayed growth trajectories by looking at several nested targeted deficiencies of the mouse HoxD cluster. Mutant pups were severely stunted during the suckling period, but many recovered after weaning. After comparing seven distinct HoxD alleles, including CRISPR/Cas9 deletions involving Haglr, we identified Hoxd3 as the critical component for the gut to maintain milk-digestive competence. This essential function could be abrogated by the dominant-negative effect of HOXD10 as shown by a genetic rescue approach, thus further illustrating the importance of posterior prevalence in Hox gene function. A role for the lncRNA Haglr in the control of postnatal growth could not be corroborated.

KEYWORDS:

CRISPR-cas9; Hox regulation; digestive system; growth control; lncRNA

PMID:
29042517
PMCID:
PMC5676926
DOI:
10.1073/pnas.1712511114
[Indexed for MEDLINE]
Free PMC Article

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