Inhibition of BMP signaling in P-Cadherin positive hair progenitor cells leads to trichofolliculoma-like hair follicle neoplasias

Lixin Kan,John A Kessler,Yijie Liu,Michael A Bonaguidi,Tammy L McGuire

doi:10.1186/1423-0127-18-92

Abstract

BackgroundSkin stem cells contribute to all three major lineages of epidermal appendages, i.e., the epidermis, the hair follicle, and the sebaceous gland. In hair follicles, highly proliferative committed progenitor cells, called matrix cells, are located at the base of the follicle in the hair bulb. The differentiation of these early progenitor cells leads to specification of a central hair shaft surrounded by an inner root sheath (IRS) and a companion layer. Multiple signaling molecules, including bone morphogenetic proteins (BMPs), have been implicated in this process.MethodsTo further probe the contribution of BMP signaling to hair follicle development and maintenance we employed a transgenic mouse that expresses the BMP inhibitor, Noggin, to disrupt BMP signaling specifically in subset of hair follicle progenitors under the control of neuron specific enolase (Nse) promoter. We then studied the skin tumor phenotypes of the transgenic mice through histology, immunohistochemistry and Western Blotting to delineate the underlying mechanisms. Double transgenic mice expressing BMP as well as noggin under control of the Nse promoter were used to rescue the skin tumor phenotypes.ResultsWe found that the transgene is expressed specifically in a subpopulation of P-cadherin positive progenitor cells in Nse-Noggin mice. Blocking BMP signaling in this cell population led to benign hair follicle-derived neoplasias resembling human trichofolliculomas, associated with down-regulation of E-cadherin expression and dynamic regulation of CD44.ConclusionsThese observations further define a critical role for BMP signaling in maintaining the homeostasis of hair follicles, and suggest that dysregulation of BMP signaling in hair follicle progenitors may contribute to human trichofolliculoma.

Highlights

Skin stem cells contribute to all three major lineages of epidermal appendages, i.e., the epidermis, the hair follicle, and the sebaceous gland
The noggin transgene is expressed in P-cadherin positive hair progenitor cells in neuron specific enolase (Nse)-Noggin mice Noggin overexpression under different promoters leads to a spectrum of phenotypes due to differing temporal and spatial patterns of transgene expression [18,19,20,21]
To begin to understand how inhibition of bone morphogenetic proteins (BMPs) signaling in this mouse model leads to tumorigenesis, we first examined the pattern of transgene expression in skin

Summary

Introduction

Skin stem cells contribute to all three major lineages of epidermal appendages, i.e., the epidermis, the hair follicle, and the sebaceous gland. The skin is a barrier that protects against the physical, chemical, and thermal assaults of the environment To serve these functions, epidermis generates an elaborate array of supportive appendages, including hair follicles (HFs), sebaceous glands, sweat glands, and nails [1]. Germline mutation of BMP2 or BMP4 leads to embryonic lethality [9,10], whereas inhibition of BMP signaling by overexpressing Noggin under control of different promoters, or by conditional knockout of BMP receptor subunits, leads to variable phenotypes. Many of these mutant animals show strong cutaneous phenotypes that resemble human skin disorders. Further study along this line will deepen our understanding of the normal role of BMP signaling in skin and supportive appendages

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