SPECIFIC ECTODERMAL ENHANCERS CONTROL THE EXPRESSION OFHoxcGENES IN DEVELOPING MAMMALIAN INTEGUMENTS

Abstract

Vertebrate Hox genes are key players in the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here we set up to analyze their elusive function in the ectodermal compartment, using the mouse limb bud as a model. We report that the HoxC gene cluster was globally co-opted to be transcribed in the distal limb ectoderm, where it is activated following the rule of temporal colinearity. These ectodermal cells subsequently produce various keratinized organs such as nails or claws.Accordingly, deletion of the HoxC cluster led to mice lacking nails (anonychia) and also hairs (alopecia), a condition stronger than the previously reported loss of function of Hoxc13, which is the causative gene of the ectodermal dysplasia 9 (ECTD9) in human patients. We further identified two ectodermal, mammalian-specific enhancers located upstream of the HoxC gene cluster, which act synergistically to regulate Hoxc gene expression in the hair and nail ectodermal organs. Deletion of these regulatory elements alone or in combination revealed a strong quantitative component in the regulation of Hoxc genes in the ectoderm, suggesting that these two enhancers may have evolved along with mammals to provide the level of HOXC proteins necessary for the full development of hairs and nails. Significance StatementIn this study, we report a unique and necessary function for the HoxC gene cluster in the development of some ectodermal organs, as illustrated both by the hair and nail phenotype displayed by mice lacking the Hoxc13 function and by the congenital anonychia (absence of nails) in full HoxC cluster mutants. We show that Hoxc genes are activated in a colinear manner in the embryonic limb ectoderm and are subsequently transcribed in developing nails and hairs. We identify two mammalian-specific enhancers located upstream of the HoxC cluster with and exclusive ectodermal specificity. Individual or combined enhancer deletions suggest that they act

CHAC1 as a novel biomarker for distinguishing alopecia from other dermatological diseases and determining its severity

“…Homoeobox Protein Hox‐C13 ( HOXC13 ) is a member of the HoxC gene cluster recruited for unique and necessary functions in the development of some ectodermal organs, including hair, nail, and filiform papilla [ 38 , 50 ]. The fact that both downregulation and upregulation of HOXC13 affect the regular expression of hard keratins specific to the hair and led to hair loss, as illustrated both by the brittle hair resulting in the alopecia phenotype, displayed by mice lacking the function of HOXC13, and by the hairless phenotype of mouse models overexpressing HOXC13, resembling ichthyosis, further highlights the vital regulatory role of HOXC13 expression levels over various keratin genes [ 51 , 52 , 53 , 54 , 55 ]. Consistent with our results, HOXC13 downregulation during AA development has been recently identified using DEG analysis [ 37 , 45 ].…”