Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification

Abstract

The mouse scaramanga (ska) mutation impairs mammary gland development such that both abrogation and stimulation of gland formation occurs. We used positional cloning to narrow the interval containing scaramanga (ska) to a 75.6-kb interval containing the distal part of the Neuregulin3 (Nrg3) gene. Within this region the only sequence difference between ska and wild-type mice is in a microsatellite repeat within intron 7. This alteration correlates with variations in Nrg3 expression profiles both at the whole embryo level and locally in the presumptive mammary region in ska mice. Localized expression of Nrg3 and its receptor, Erbb4, in the presumptive mammary region around the future bud site prior to morphological appearance of buds and the expression of bud epithelial markers further support an inductive role. Finally, Neuregulin3 (Nrg3)-soaked beads can induce expression of the early bud marker Lef1 in mouse embryo explant cultures, and epithelial bud formation can be observed histologically, suggesting that initiation of mammary bud development occurs. Taken together, these results indicate that a Neuregulin signaling pathway is involved in specification of mammary gland morphogenesis and support the long-held view that mesenchymal signal(s) are responsible for mammary gland inductive/initiating events.[Keywords: Mammary gland development; Neuregulin3; specification] Supplemental material is available at http://www.genesdev.org.

HOXC8 initiates an ectopic mammary program by regulating Fgf10 and Tbx3 expression, and Wnt/β-catenin signaling

“…Supernumerary mammary placode development has previously been reported in experimental mice, but always within or near the wild-type mammary line, never in unique regions (Ahn et al, 2013;Chu et al, 2004;Howard et al, 2005;Mustonen et al, 2003). This difference between our and previous mouse models of mammary induction underscores the ability of ectopic Hoxc8 to initiate a mammary program, thus altering mesenchymal-ectodermal communication at the earliest stages of mammary line potentiation.…”

Gli3-mediated somiticFgf10expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes

“…We show here that placode 3 is most sensitive to a reduction of somitic Fgf10. Similarly, placode 3 is more sensitive than placodes 2 and 4 to loss of Gli3 (this report) or neuregulin 3 (Howard et al, 2005). Gland 3 is also the gland most frequently absent in wild-type mice (Little and McDonald, 1945).…”

“…Few genes are known to be involved in early mammogenesis (Mustonen et al, 2003;Chu et al, 2004;Mustonen et al, 2004;Howard et al, 2005;Jerome-Majewska et al, 2005). Most of them are expressed in the ectoderm, yet factors from the underlying mesenchyme initiate mammogenesis (Veltmaat et al, 2003).…”

BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction

“…Our understanding of the molecular events underpinning early mammary development remains rudimentary, but recent work has begun to characterize some of the mediators of these crucial epithelial-mesenchymal interactions. Like in other organs, members of the FGF, hedgehog, WNT and EGF growth factor signaling pathways play important roles in the patterning and formation of the initial mammary placodes Davenport et al, 2003;Eblaghie et al, 2004;Hatsell and Cowin, 2006;Howard et al, 2005;Mailleux et al, 2002;Veltmaat et al, 2004;Veltmaat et al, 2006). As discussed below, parathyroid hormone related protein (PTHrP; also known as parathyroid hormone-like peptide, Pthlh) and its receptor are important to the formation of the mammary mesenchyme and outgrowth of the nascent mammary ducts (Hens and Wysolmerski, 2005).…”