Shh expression is required for embryonic hair follicle but not mammary gland development

Abstract

The embryonic mammary gland and hair follicle are both derived from the ventral ectoderm, and their development depends on a number of common fundamental developmental pathways. While the Hedgehog (Hh) signaling pathway is required for hair follicle morphogenesis, the role of this pathway during embryonic mammary gland development remains undetermined. We demonstrate here that, unlike the hair follicle, both Shh and Ihh are expressed in the developing embryonic mouse mammary rudiment as early as E12.5. In Shh(-/-) embryos, hair follicle development becomes arrested at an early stage, while the mammary rudiment, which continues to express Ihh, develops in a manner indistinguishable from that of wild-type littermates. The five pairs of mammary buds in Shh(-/-) female embryos exhibit normal branching morphogenesis at E16.5, forming a rudimentary ductal structure identical to wild-type embryonic mammary glands. We further demonstrate that loss of Hh signaling causes altered cyclin D1 expression in the embryonic dermal mesenchyme. Specifically, cyclin D1 is expressed at E14.5 principally in the condensed mesenchymal cells of the presumptive hair follicles and in both mesenchymal and epithelial cells of the mammary rudiments in wild-type and Shh-deficient embryos. By E18.5, robust cyclin D1 expression is maintained in mammary rudiments of both wild-type and Shh-deficient embryos. In hair follicles of wild-type embryos by E18.5, cyclin D1 expression switches to follicular epithelial cells. In contrast, strong cyclin D1 expression is observed principally in the mesenchymal cells of arrested hair follicles in Shh(-/-) embryos at E18.5. These data reveal that, despite the common embryonic origin of hair follicles and mammary glands, distinct patterns of Hh-family expression occur in these two tissues. Furthermore, these data suggest that cyclin D1 expression in the embryonic hair follicle is mediated by both Hh-independent and Hh-dependent mechanisms.

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

“…Previous work showed that hedgehog effector molecules Gli-2 and Patched-1 function in the stroma to regulate mammary development (Lewis et al, 1999(Lewis et al, , 2001). However, hedgehog ligands Shh and Ihh do not regulate mammary development, as described earlier (Gallego et al, 2002;Michno et al, 2003). Our data suggest that it may be epithelialderived Dhh that activates stromal hedgehog effector molecules to regulate mammary branching morphogenesis.…”

“…Little is known about the molecular basis of branching in the mammary gland. The hedgehog members Shh and Ihh are not necessary for mammary branching as ShhϪ/Ϫ and IhhϪ/Ϫ rescued mammary anlagen can give rise to a normal mammary gland (Gallego et al, 2002;Michno et al, 2003). No members of the Wnt signaling pathway have been shown to be specifically expressed in the TEBs or necessary for TEB-induced (primary-secondary) branching, although Wnt-4 is necessary for side (tertiary) branching (Brisken et al, 2000).…”

Comparative Mechanisms of Branching Morphogenesis in Diverse Systems

“…Since both Gli2 and Ptc-1 are expressed in the stroma, HH signaling must act upon the epithelium via an unidentified stromal factor(s). However, mammary glands lacking either Shh or Indian HH (Ihh) show no defects in postnatal branching morphogenesis [81,82]. Thus, it remains unclear at present whether Shh and Ihh play a redundant role in mammary branching.…”

Targeted Expression of GLI1 in the Mammary Gland Disrupts Pregnancy-induced Maturation and Causes Lactation Failure

“…However, a small portion of fully committed alveolar cells escape the involution process and function as alveolar progenitors during subsequent pregnancies (18). The Hh homologues Shh, Ihh, and Dhh are expressed in the mouse mammary gland (19,20). Most likely, Ihh and Shh have redundant functions in mammary gland development during embryogenesis, since the embryonic mammary gland develops normally in Shh and Ihh knock-out mice (21,22).…”