Evidence That the Satin Hair Mutant Gene Foxq1 Is among Multiple and Functionally Diverse Regulatory Targets for Hoxc13 during Hair Follicle Differentiation

Abstract

It is increasingly evident that the molecular mechanisms underlying hair follicle differentiation and cycling recapitulate principles of embryonic patterning and organ regeneration. Here we used Hoxc13-overexpressing transgenic mice (also known as GC13 mice), known to develop severe hair growth defects and alopecia, as a tool for defining pathways of hair follicle differentiation. Gene array analysis performed with RNA from postnatal skin revealed differential expression of distinct subsets of genes specific for cells of the three major hair shaft compartments (cuticle, cortex, and medulla) and their precursors. This finding correlates well with the structural defects observed in each of these compartments and implicates Hoxc13 in diverse pathways of hair follicle differentiation. The group of medulla-specific genes was particularly intriguing because this included the developmentally regulated transcription factor-encoding gene Foxq1 that is altered in the medulladefective satin mouse hair mutant. We provide evidence that Foxq1 is a downstream target for Hoxc13 based on DNA binding studies as well as co-transfection and chromatin immunoprecipitation assays. Expression of additional medulla-specific genes down-regulated upon overexpression of Hoxc13 requires functional Foxq1 as their expression is ablated in hair follicles of satin mice. Combined, these results demonstrate that Hoxc13 and Foxq1 control medulla differentiation through a common regulatory pathway. The apparent regulatory interactions between members of the mammalian Hox and Fox gene families shown here may establish a paradigm for "cross-talk" between these two conserved regulatory gene families in different developmental contexts including embryonic patterning as well as organ development and renewal.

The disruption of Sox21-mediated hair shaft cuticle differentiation causes cyclic alopecia in mice

“…This might indicate that the cuticle and cortex cells are derived from common precursors and further that Sox21 might be involved in a lineage restriction mechanism. Recently, it has been shown that Hoxc13 is expressed in the precursors of all 3 hair shaft-forming compartments (cuticle, cortex, and medulla) and mainly regulates the expression of medulla-specific genes by directly regulating Foxq1 expression (18). However, the expression of both Hoxc13 and Foxq1 was found unaltered in the Sox21-null mouse, indicating that Sox21 functions downstream or in parallel with the Hoxc13 cascade in the hair follicle.…”

“…4A). Among these, we identified keratin and its related genes, Krt32, Krt82, Krtap5-1, Krtap5-4, and Krtap12-1, which are known to be expressed only in the Cuh (9,10,17,18) and validated their down-regulation in Sox21 Ϫ/Ϫ skin by quantitative PCR (Q-PCR) (Fig. 4B).…”

Fundamental hair follicle biology and fine fibre production in animals

“…Defects in Hox C13 expression have been shown to give rise to loss of hair in mutant mice. Potter et al (2006) also showed that the regulatory transcription factor-encoding gene Foxq, is a downstream target for Hox C13 and acting through a common regulatory pathway controls differentiation of hair follicle medulla. Other transcriptional regulatory molecules include (a) the Sox 9 gene product, which has been ascribed an essential role in development of ORS and stem cell compartment of murine hair follicles in which it has continuous expression (Vidal et al, 2005), (b) Foxe 1, detected in the lower undifferentiated region of the HF and involved in hair follicle morphogenesis, as an apparent downstream target of the Shh/ Gli pathway (Brancaccio et al, 2004) and (c) Gata 3 (Kaufman et al, 2003) which has been ascribed a role in early specification of basal cells towards IRS as opposed to hair shaft lineage.…”

“…An essential role for the transcriptional repressor Cutl 1 has been indicated in the development of IRS (Ellis et al, 2001). Similarly, the Hox family of transcription factors, which are usually expressed sequentially according to spatial position and time with respect to their positions in the Hox complex has been ascribed a role in regulation of patterning and developmental morphology of hair follicles (and other tissues of the integument) (Potter et al, 2006). Expression of Hox C13 was detected in medulla, cortex, IRS, companion layer and upper inner ORS.…”

FOXQ1 (forkhead box Q1)

“…In mouse Foxq1 has been reported to be regulated by Hoxa1 (Martinez-Ceballos et al, 2005), Hoxc13 (Potter et al, 2006) and Tgfβ (Zhang et al, 2011). In human FOXQ1 has been shown to be a target of the Wnt pathway Xia et al, 2014).…”