TRPS1 and Its Target Gene SOX9 Regulate Epithelial Proliferation in the Developing Hair Follicle and are Associated with Hypertrichosis

2012-11-03 11:13:05

PLoS Genet; 2012 Nov; 8(11):e1003002

Katherine A. Fantauzzo, Mazen Kurban, Brynn Levy, Angela M. Christiano

Author Summary

The various ectodermal appendages found in nature have evolved over time to allow organisms to better adapt to their environment. These include hair, feathers, scales, nails, teeth, beaks, horns, and a wide array of eccrine glands. The hair follicle is an ectodermal appendage unique to mammals that serves a wide array of functions, including thermoregulation, sensation, and communication. Hair follicle formation begins during embryogenesis through a series of interactions between adjacent epithelial and mesenchymal tissues. The mechanisms by which the diverse cells types of the hair follicle arise and the contribution of progenitor cells to the processes of growth and differentiation are not completely understood. Here, we have identified the transcription factor Trps1 as a novel regulator of epithelial proliferation in the developing hair follicle, through its control of Sox9, a gene known to regulate hair follicle stem cells. Moreover, we demonstrate that duplicated genetic material upstream of SOX9, which alters expression of the gene, results in a rare form of hereditary hair overgrowth syndrome in humans.


Hypertrichosis is defined as excessive hair growth for a particular site of the body or age of a patient that is not hormone-dependent. Hypertrichoses are characterized on the basis of multiple criteria: cause (genetic or acquired), age of onset, extent of hair distribution (universal or localized) and affected sites. Hereditary hypertrichoses are very rare in humans, affecting as few as one in one billion individuals. Whereas many additional anomalies are associated with hypertrichosis, only a subset of disorders with congenital hypertrichosis present with excessive hair as the primary clinical feature. These include hypertrichosis universalis (OMIM 145700), Ambras type (OMIM 145701), X-linked hypertrichosis (OMIM 307150) and generalized hypertrichosis terminalis with or without gingival hyperplasia (OMIM 135400).

We previously demonstrated that a position effect on the zinc-finger transcription factor TRPS1 is associated with two hypertrichosis models, Ambras syndrome (AS) in humans and the Koala phenotype in mice. Consistent with a causative role for Trps1 in hypertrichosis, the protein is expressed in the nuclei of mesenchyme-derived dermal papilla cells and the proliferative epithelial cells of human and mouse hair follicles.

Heterozygous germline mutations in TRPS1 on chromosome 8q23 in humans result in autosomal dominant inheritance of trichorhinophalangeal syndrome types I and III (TRPS1 I, OMIM 190350; TRPS III, OMIM 190351), which are characterized by sparse and slow-growing scalp hair, as well as craniofacial and skeletal abnormalities. Correspondingly, homozygous mutant mice in which the GATA-type zinc-finger domain of Trps1 was deleted (Trps1Δgt/Δgt) were reported to have a number of hair follicle, craniofacial and skeletal defects that mirror the phenotypic characteristics of human TRPS patients. Trps1Δgt/Δgt mice die within six hours of birth due to respiratory failure stemming from thoracic skeletal defects. Homozygous mutant mice were reported to completely lack vibrissae follicles during late gestation. In addition, neonatal Trps1Δgt/Δgt mice had an approximately 50 percent reduction in dorsal pelage follicle density compared to their wild-type littermates, whereas heterozygous mice had an intermediate pelage phenotype. Trps1-/- null mice were subsequently generated and were similarly reported to display severe hair follicle abnormalities.

We recently performed a detailed histological analysis of early vibrissa follicle morphogenesis in Trps1Δgt/Δgt embryos from E12.5–E13.5. We found that the mutant vibrissae were reduced in number, irregularly spaced and developmentally delayed when compared to their wild-type counterparts. Additional analyses revealed that these defects were likely due to disruption of Wnt signaling and the misexpression of several transcription factors and extracellular matrix proteins regulated by Trps1 in the mutant whisker pads. While these studies collectively revealed a requirement for Trps1 during early vibrissa follicle formation, they did not address the mechanism(s) underlying the follicle degeneration observed later in these embryos.

Hypertrichosis had previously been reported in a case of partial trisomy 17q22-qter associated with a de novo unbalanced translocation, suggesting that the distal portion of human chromosome 17q may contain dosage-sensitive genes that contribute to excessive hair growth. Recently, a series of microdeletions were reported on chromosome 17q24.2–q24.3 in three cases of familial congenital generalized hypertrichosis terminalis with gingival hyperplasia (CGHT), as well as a de novo microduplication within this same region in a case of sporadic CGHT. The minimal region common to each of these cases lies 2.5Mb upstream of SOX9, a gene previously shown to be required for the specification and maintenance of hair follicle stem cells in mice.

Here, we uncover a novel transcriptional hierarchy in the hair follicle in which Trps1 regulates Sox9 to control epithelial proliferation in the developing vibrissa follicle in mice. Furthermore, we identify a copy number variation less than 1Mb upstream of SOX9 in a family with CGHT that significantly decreases expression of the gene in the hair follicle, providing significant insight into the pathology of human hypertrichosis.


Late morphogenesis vibrissa follicle abnormalities in Trps1Δgt/Δgt mutant embryos

We began by performing a thorough histological analysis of vibrissa follicle morphogenesis during late gestation in Trps1Δgt/Δgt embryos. Similar to the defects observed during early morphogenesis in these embryos, the mutant vibrissae follicles that were present at E16.5 were reduced in number, irregularly spaced and smaller than wild-type vibrissae, with evidence of both an epithelial peg and dermal condensate (Figure 1A–1E). However, the development of these mutant vibrissae follicles was subsequently arrested, and they degenerated after peg downgrowth had been initiated so that they were rarely visible at birth (Figure 1F–1J). Interestingly, heterozygous Trps1+/Δgt embryos displayed an intermediate vibrissae phenotype (Figure 1D and 1G), with vibrissae follicles that were slightly larger, more advanced in development and greater in number than those detected in Trps1Δgt/Δgt mutant embryos (Figure 1E and 1H), indicating a dose-dependent requirement for Trps1 in multiple hair types. We additionally confirmed the reduction in pelage follicle density reported in homozygous mutant animals (Figure 1K and 1L).

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