Barx2 functions through distinct corepressor classes to regulate hair follicle remodeling

Abstract

The hair-growth cycle, a complex biological system requiring coordinate alterations in gene expression and cellular behavior, provides a challenging model for investigating the interplay of specific transcriptional regulation events. Here we report that the Barx2 homeodomain factor serves as a regulator of hair follicle remodeling (catagen), and loss of Barx2 in mice causes a defect both in the initiation and progression of catagen, resulting in a protracted first catagen, and later, causing short hair in adult gene-deleted mice. Barx2 negatively regulates its own promoter, and our study highlights the role of Barx2 as a repressor in the skin that can, unexpectedly, functionally interact with two WD40-domain factors distantly related to the yeast corepressor Tup1. These two corepressors, transducin-like enhancer of split and transducin ␤-like 1, function through distinct and independent interactions with Barx2 for the repression of gene targets, including the Barx2 gene itself, emphasizing the roles of complementary repression strategies in engrailed homology-1 motif-containing homeodomain factors. Together, our data suggest that the hairremodeling defect of Barx2 mutant mice could be explained, in part, by failure to repress one or more critical target genes.A distinctive feature of the hair follicle is its periodic regeneration and degeneration throughout the lifetime of the organism in cycles of three phases: anagen, catagen, and telogen. In mice, hair follicle morphogenesis begins late in development and continues through growth, or anagen, of the first pelage until Ϸ2 weeks after birth. The final length of the hair is genetically determined by the period spent in anagen, with hair-generating cells of the bulb having a finite proliferative capacity that is influence by factors from the dermal papilla and surrounding tissues. Anagen terminates with the destruction of the growing part of the follicle in a remodeling process called catagen. Thereafter, a resting period, or telogen, intervenes with the finished hair normally retained in the diminutive follicle, until anagen reinitiates with the start of a new cycle of hair growth (1, 2). Two synchronous cycles of hair growth occur in juvenile mice, with consecutive waves of anagen-catagen-telogen moving from neck to tail, and thereafter only smaller patches of follicles cycle together in adult mice. From the human perspective, hair follicle remodeling is important because changes in the hair cycle underlie most disorders involving unwanted hair growth or loss (3, 4). Evidence is also emerging that hair cycling and wound healing share some basic molecular strategies (5).The transcriptional control of skin and hair development, and regulation of postnatal, cycling hair follicles, represents a complex system involving the coordinated actions of many intracellular signaling molecules and transcription factors. Recently, expression profiling has been used to systematically identify hair-cycle-associated genes and cluster them into major classes of expression over the...

Barx2 and Fgf10 regulate ocular glands branching morphogenesis by controlling extracellular matrix remodeling

“…At E16-16.5, Barx2 protein was detected in LGs by immunostaining (Fig. 1C,D) and by -galactosidase histochemistry in heterozygous Barx2-lacZ knock-in mouse embryos (Olson et al, 2005) (Fig. 1E).…”

“…-/-mice show eyelid fusion defects Barx2 -/-mice (Olson et al, 2005) showed multiple defects of ocular gland and eyelid development (Figs 2, 3). The development of mouse eyelids starts at E13.0-13.5, and complete eyelid closure is accomplished by E16.0-16.5.…”

“…The sequences encoding the homeodomain and C-terminal region of Barx2 were deleted and the 134 amino acid N-terminal Barx2 region was fused in frame to -galactosidase (Olson et al, 2005). Mice were genotyped by genomic PCR (Olson et al, 2005).…”

“…The sequences encoding the homeodomain and C-terminal region of Barx2 were deleted and the 134 amino acid N-terminal Barx2 region was fused in frame to -galactosidase (Olson et al, 2005). Mice were genotyped by genomic PCR (Olson et al, 2005). lacZ expression in Barx2 -/--and Barx2 +/--lacZ knock-in mice and Pax6-lacZ transgenic mice was assessed by -galactosidase histochemistry using established protocols (Dean et al, 2004;Faber et al, 2002;Song et al, 1996).…”

“…We and others have shown that the homeodomain transcription factor Barx2, which is related to the Drosophila Bar family genes, is expressed in several epithelial tissues that develop through branching morphogenesis such as lung, kidney, mammary gland, and lacrimal and salivary gland primordia (Herring et al, 2001;Jones et al, 1997;Olson et al, 2005;Sander et al, 2000;Sellar et al, 2001;Sellar et al, 2002;Stevens and Meech, 2006). However, the role of Barx2 during branching morphogenesis has not been determined.…”