Control of growth and gut maturation by <i>HoxD</i> genes and the associated lncRNA <i>Haglr</i>.

Abstract

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