Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis

Abstract

SUMMARYMutations in TRPS1 cause trichorhinophalangeal syndrome types I and III, which are characterized by sparse scalp hair in addition to craniofacial and skeletal abnormalities. Trps1 is a vertebrate transcription factor that contains nine zinc-finger domains, including a GATA-type zinc finger through which it binds DNA. Mice in which the GATA domain of Trps1 has been deleted (Trps1) have a reduced number of pelage follicles and lack vibrissae follicles postnatally. To identify the transcriptional targets of Trps1 in the developing vibrissa follicle, we performed microarray hybridization analysis, comparing expression patterns in the whisker pads of wild-type versus Trps1 ⌬gt/⌬gt embryos. We identified a number of transcription factors and Wnt inhibitors among transcripts downregulated in the mutant embryos and several extracellular matrix proteins that were upregulated in the mutant samples, and demonstrated that target gene expression levels were altered in vivo in Trps1 ⌬gt/⌬gt vibrissae. Unexpectedly, we discovered that Trps1 can directly bind the promoters of its target genes to activate transcription, expanding upon its established role as a transcriptional repressor. Our findings identify Trps1 as a novel regulator of the Wnt signaling pathway and of early hair follicle progenitors in the developing vibrissa follicle.

Dual Role of the Trps1 Transcription Factor in Dentin Mineralization

“…This mechanism incorporates the findings from our in vitro studies into the well established molecular function of Trps1 as a transcriptional repressor (31)(32)(33)(34)(35). We cannot definitively rule out the possibility that in preodontoblasts Trps1 directly activates a subset of mineralization genes, as it has been demonstrated for Wnt pathway genes in hair follicle progenitor cells (36). However, thus far, there is no evidence that Trps1 can act as a transcriptional activator in cells other than hair follicle progenitors.…”

“…Trps1 is a unique zinc finger protein that belongs to the GATA family of transcription factors (31). Although a majority of studies have demonstrated that Trps1 is a transcriptional repressor, recently it has been shown that during hair formation Trps1 can activate expression of Wnt pathway genes (32)(33)(34)(35)(36). Mutations of the TRPS1 gene in humans cause the craniofacial and skeletal dysplasia tricho-rhino-phalangeal syndrome (TRPS) and Ambras syndrome (37,38).…”

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

“…In early hair follicle progenitors, TRPS1 is a transcriptional activator of genes that inhibit Wnt signaling (56), whereas it is a repressor of RUNX2, a gene important for osteoclast differentiation and maturation (57). Moreover, in odontoblast development, Trsp1 is an inhibitor of Dspp expression (58), whereas in chondrocytes, Trps1 controls proliferation and survival by repressing Stat3 expression (59).…”

“…Because TRPS1 represses transcription from GATA-containing binding sites (43,(56)(57)(58)(59), we searched for conserved GATA sites in the promoter regions of SERPINE1 and SERPINB2. We then designed oligonucleotides specific for these binding sites.…”

Current Genetics in Hair Diseases

“…Furthermore, it has recently been reported that Trps1 plays crucial roles in regulating the expression of several Wnt inhibitors and various transcription factors during vibrissa follicle morphogenesis in mice [75]. In humans, mutations in the TRPS1 gene are known to cause trichorhinophalangeal syndrome type I (TRPS I; MIM 190350) or type III (TRPS III; MIM 190351), both of which show an autosomal dominant inheritance trait, and are characterized by sparse hair and a number of craniofacial and skeletal abnormalities, such as peer-shaped nose and brachydactyly.…”