Edar is a downstream target of beta-catenin and drives collagen accumulation in the mouse prostate.

Kyle A Wegner,Chad M Vezina,Lisa L Abler,Brett R Mueller,M Mark Taketo,Vatsal Mehta,Kimberly P Keil,Jeanette A Johansson,Denis J Headon,Paul C Marker

doi:10.1242/bio.037945

Abstract

ABSTRACTBeta-catenin (CTNNB1) directs ectodermal appendage spacing by activating ectodysplasin A receptor (EDAR) transcription, but whether CTNNB1 acts by a similar mechanism in the prostate, an endoderm-derived tissue, is unclear. Here we examined the expression, function, and CTNNB1 dependence of the EDAR pathway during prostate development. In situ hybridization studies reveal EDAR pathway components including Wnt10b in the developing prostate and localize these factors to prostatic bud epithelium where CTNNB1 target genes are co-expressed. We used a genetic approach to ectopically activate CTNNB1 in developing mouse prostate and observed focal increases in Edar and Wnt10b mRNAs. We also used a genetic approach to test the prostatic consequences of activating or inhibiting Edar expression. Edar overexpression does not visibly alter prostatic bud formation or branching morphogenesis, and Edar expression is not necessary for either of these events. However, Edar overexpression is associated with an abnormally thick and collagen-rich stroma in adult mouse prostates. These results support CTNNB1 as a transcriptional activator of Edar and Wnt10b in the developing prostate and demonstrate Edar is not only important for ectodermal appendage patterning but also influences collagen organization in adult prostates.This article has an associated First Person interview with the first author of the paper.

Highlights

The mouse prostate derives from the urogenital sinus (UGS), a fetal structure at the base of the bladder and consisting of endoderm-derived epithelium, mesoderm-derived mesenchyme, and other cell types
Ectodysplasin A receptor (Edar) mRNA localizes to prostatic epithelium during bud formation and branching morphogenesis (Keil et al, 2012a)
To determine whether other pathway components are expressed, In situ hybridization (ISH) was used to visualize the ectodysplasin A receptor (EDAR) ligand Eda and the putative downstream target of EDAR signaling (Wnt10b) during the periods coinciding with bud elongation (18 days post conception, dpc) and branching morphogenesis

Summary

Introduction

The mouse prostate derives from the urogenital sinus (UGS), a fetal structure at the base of the bladder and consisting of endoderm-derived epithelium, mesoderm-derived mesenchyme, and other cell types. Prostate development is initiated by androgen-induced signals from UGS mesenchyme (Cunha and Lung, 1978; Goldstein and Wilson, 1975; Lasnitzki and Mizuno, 1980). The Wingless/beta-catenin (Wnt/CTNNB1) is an androgen sensitive signaling pathway critical for prostatic bud formation (He et al, 2018). CTNNB1 and its target genes are present in prostatic buds from the earliest stage of prostate development and continuing at least through postnatal branching morphogenesis (Francis et al, 2013, Simons et al, 2012). Chemical inhibition or genetic deletion of CTNNB1 in UGS epithelium completely prevents prostatic bud formation (Mehta et al, 2013; Simons et al, 2012), while excessive CTNNB1 activation by genetic gain-offunction increases the inter-bud interval and reduces the quantity of prostatic buds formed (Mehta et al, 2013). How CTNNB1 is activated during prostate development and how its activity is restricted to prostatic bud tips is not fully understood

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