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Abstract Hoxa5plays numerous roles in development, but its downstream molecular effects are mostly unknown. We applied bulk RNA-seq assays to characterize the transcriptional impact of the loss ofHoxa5gene function in seven different biological contexts, including developing respiratory and musculoskeletal tissues that present phenotypes inHoxa5mouse mutants. This global analysis revealed few common transcriptional changes, suggesting that HOXA5 acts mainly via the regulation of context-specific effectors. However,Hoxgenes themselves appeared as potentially conserved targets of HOXA5 across tissues. Notably, a trend toward reduced expression ofHoxAgenes was observed inHoxa5null mutants in several tissue contexts. Comparative analysis of epigenetic marks along theHoxAcluster in lung tissue from two differentHoxa5mutant mouse lines revealed limited effect of either mutation indicating thatHoxa5gene targeting did not significantly perturb the chromatin landscape of the surroundingHoxAcluster. Combined with the shared impact of the twoHoxa5mutant alleles on phenotype andHoxexpression, these data argue against the contribution of localciseffects toHoxa5mutant phenotypes and support the notion that the HOXA5 protein acts intransin the control ofHoxgene expression. 

Brown adipose tissue (BAT) plays critical thermogenic, metabolic and endocrine roles in mammals, and aberrant BAT function is associated with metabolic disorders including obesity and diabetes. The major BAT depots are clustered at the neck and forelimb levels, and arise largely within the dermomyotome of somites, from a common progenitor with skeletal muscle. However, many aspects of BAT embryonic development are not well understood. Hoxa5 patterns other tissues at the cervical and brachial levels, including skeletal, neural and respiratory structures. Here, we show that Hoxa5 also positively regulates BAT development, while negatively regulating formation of epaxial skeletal muscle. HOXA5 protein is expressed in embryonic preadipocytes and adipocytes as early as embryonic day 12.5. Hoxa5 null mutant embryos and rare, surviving adults show subtly reduced iBAT and sBAT formation, as well as aberrant marker expression, lower adipocyte density and altered lipid droplet morphology. Conversely, the epaxial muscles that arise from a common dermomyotome progenitor are expanded in Hoxa5 mutants. Conditional deletion of Hoxa5 with Myf5/Cre can reproduce both BAT and epaxial muscle phenotypes, indicating that HOXA5 is necessary within Myf5- positive cells for proper BAT and epaxial muscle development. However, recombinase-based lineage tracing shows that Hoxa5 does not act cell-autonomously to repress skeletal muscle fate. Interestingly, Hoxa5 -dependent regulation of adipose-associated transcripts is conserved in lung and diaphragm, suggesting a shared molecular role for Hoxa5 in multiple tissues. Together, these findings establish a role for Hoxa5 in embryonic BAT development.