Dermal Blimp1 Acts Downstream of Epidermal TGFβ and Wnt/β-Catenin to Regulate Hair Follicle Formation and Growth

Stephanie B Telerman,Emanuel Rognoni,Inês Sequeira,Angela Oliveira Pisco,Beate M Lichtenberger,Oliver J Culley,Priyalakshmi Viswanathan,Ryan R Driskell,Fiona M Watt

doi:10.1016/j.jid.2017.06.015

Stephanie B Telerman, Emanuel Rognoni + Show 7 more

Open Access

https://doi.org/10.1016/j.jid.2017.06.015

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Abstract

B-lymphocyte-induced maturation protein 1 (Blimp1) is a transcriptional repressor that regulates cell growth and differentiation in multiple tissues, including skin. Although in the epidermis Blimp1 is important for keratinocyte and sebocyte differentiation, its role in dermal fibroblasts is unclear. Here we show that Blimp1 is dynamically regulated in dermal papilla cells during hair follicle (HF) morphogenesis and the postnatal hair cycle, preceding dermal Wnt/β-catenin activation. Blimp1 ablation in E12.5 mouse dermal fibroblasts delayed HF morphogenesis and growth and prevented new HF formation after wounding. By combining targeted quantitative PCR screens with bioinformatic analysis and experimental validation we demonstrated that Blimp1 is both a target and a mediator of key dermal papilla inductive signaling pathways including transforming growth factor-β and Wnt/β-catenin. Epidermal overexpression of stabilized β-catenin was able to override the HF defects in Blimp1 mutant mice, underlining the close reciprocal relationship between the dermal papilla and adjacent HF epithelial cells. Overall, our study reveals the functional role of Blimp1 in promoting the dermal papilla inductive signaling cascade that initiates HF growth.

Highlights

B-lymphocyte-induced maturation protein 1 (Blimp1; Prdm1) is a zinc finger transcription factor that is first expressed at mouse embryonic (E) day 6.25 of development, and mice lacking Blimp1 die at E10.5 due to placental insufficiency (Vincent et al, 2005)
Dynamic expression of Blimp1 in the dermal papilla (DP) We first performed a characterization of Blimp1 expression during hair follicle (HF) morphogenesis and the hair cycle (HC)
Skin sections from PDGFRaH2BeGFP mice immunostained for (a) GFP and Blimp1 or (b) Lef1 and Blimp1. (c) TOPGFP back skin sections immunolabeled for GFP and Blimp1. Blimp1 expression during postnatal HC. (d, e) Immunostaining of adult back skin for PDGFRa and Blimp1 at the indicated age or HC stage. (f) TOPGFP skin sections immunolabeled for GFP and Blimp1 at the indicated HC stage. (g) Immunostaining of human embryonic skin for Krt14 and Blimp1

Summary

Introduction

B-lymphocyte-induced maturation protein 1 (Blimp; Prdm1) is a zinc finger transcription factor that is first expressed at mouse embryonic (E) day 6.25 of development, and mice lacking Blimp die at E10.5 due to placental insufficiency (Vincent et al, 2005). Blimp is highly expressed from E16.5 in developing hair follicles (HFs), sebaceous glands, and interfollicular epidermis (Chang and Calame, 2002). Epidermal deletion of Blimp causes multiple differentiation defects (Kretzschmar et al, 2014), including interfollicular epidermal hyperplasia (Chiang et al, 2013), sebaceous gland enlargement (Horsley et al, 2006), and impaired epidermal barrier formation (Magnusdottir et al, 2007). Blimp is first expressed at E14.5 in the condensates of fibroblasts that will form the HF dermal papilla (DP) (Lesko et al, 2013; Robertson et al, 2007). When Blimp is deleted in Sox2þ cells, whiskers do not develop (Robertson et al, 2007)

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