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

Abstract

Little is known about the regulation of cell fate decisions that lead to the formation of five pairs of mammary placodes in the surface ectoderm of the mouse embryo. We have previously shown that fibroblast growth factor 10 (FGF10) is required for the formation of mammary placodes 1, 2, 3 and 5. Here, we have found that Fgf10 is expressed only in the somites underlying placodes 2 and 3, in gradients across and within these somites. To test whether somitic FGF10 is required for the formation of these two placodes, we analyzed a number of mutants with different perturbations of somitic Fgf10 gradients for the presence of WNT signals and ectodermal multilayering, markers for mammary line and placode formation. The mammary line is displaced dorsally, and formation of placode 3 is impaired in Pax3 ILZ/ILZ mutants, which do not form ventral somitic buds. Mammary line formation is impaired and placode 3 is absent in Gli3Xt-J/Xt-J and hypomorphic Fgf10 mutants, in which the somitic Fgf10 gradient is shortened dorsally and less overall Fgf10 is expressed, respectively. Recombinant FGF10 rescued mammogenesis in Fgf10 -/-and Gli3Xt-J/Xt-J flanks. We correlate increasing levels of somitic FGF10 with progressive maturation of the surface ectoderm, and show that full expression of somitic Fgf10, co-regulated by GLI3, is required for the anteroposterior pattern in which the flank ectoderm acquires a mammary epithelial identity. We propose that the intra-somitic Fgf10 gradient, together with ventral elongation of the somites, determines the correct dorsoventral position of mammary epithelium along the flank.

The developmental basis of bat wing muscle

“…Through comparative expression analysis of the genes that are known to regulate limb morphogenesis, we found Fgf10 signalling is likely involved in wing membrane development and patterning of the wing muscles. As reported in murine embryogenesis 17 , Fgf10 was expressed at the otic vesicle, pharyngeal arches and limb mesenchyme, as well as lateral plate mesoderm of the flank region of bat embryos at stage 13 ( Fig. 4a-c).…”

“…Interestingly, Fgf10 continued to be expressed in the lateral plate-derived mesenchyme at the anterior-proximal part of the forelimb, flank and posterior-proximal part of hind limb of bat embryos at stage 13L and 14 (Figs 4d,f and 5a-c; Supplementary Fig. S2), although expression of Fgf10 ceased in corresponding tissues of stage-matched mouse, marsupial opossum and chick embryos [17][18][19] . We also examined expression of Fgfr2IIIb that encodes the receptor of Fgf10 in bat embryos, and detected its expression in epidermis over the flank region of Fgf10-expressing lateral plate mesoderm, as well as in epidermis of the limb buds and lateral plate mesoderm anterior to the forelimb bud at stage 13L (Fig.…”

Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development

“…The Fgf10 LacZ mouse reports Fgf10 expression and also results in a Fgf10 hypomorph as demonstrated by the phenotype of Fgf10 LacZ/2 (one copy of Fgf10 null and one copy of Fgf10 LacZ ) embryos. These embryos display decreased lung branching [12] as well as mammary gland [10] and limb abnormalities (Hajihosseini and Bellusci, unpublished results) consistent with decreased Fgf10 expression.…”

“…The LacZ cassette was mapped and found to be integrated within regulatory elements lying 114 kb upstream of the endogenous Fgf10 coding sequence [7]. LacZ expression pattern observed in these mice closely mimics Fgf10 expression in the heart, lung, gut, mammary glands and brain [4,5,7,8,9,10,11]. The Fgf10 LacZ mouse reports Fgf10 expression and also results in a Fgf10 hypomorph as demonstrated by the phenotype of Fgf10 LacZ/2 (one copy of Fgf10 null and one copy of Fgf10 LacZ ) embryos.…”

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

“…In analogy mammary gland development is dependent on epithelial-mesenchymal interactions and the Hh pathway is emerging as one important factor during mammary gland development (13)(14)(15)(16)(17). Development of the mouse mammary gland is initiated around day 10.5 of embryonic development with the formation of bilateral milk lines running between the fore and hind limbs.…”