s18 is expressed in the myoepithelium downstream of Wnt4 secretion induced by ER/PR signaling luminal sensor cells (Fig. [9](#Fig9){ref-type="fig"}). The myoepithelial cells respond by canonical Wnt signaling activation and link luminal hormone receptor signaling to stromal changes with functional consequences. Our finding that altered BM composition affects MaSCs shows that the BM is a central part of the stem cell niche and a critical determinant of stem cell function.Fig. 9Working model of Adamts18 as a modulator of mammary gland development.A schematic representation of the mammary acinar wall shows the spatial relationship between luminal cells, myoepithelial cells, BM and the surrounding interstitial ECM. Estrogen and progesterone induce Adamts18 production in myoepithelial cells via Wnt4-stimulated canonical Wnt signaling. Adamts18 remodels the BM and/or interstitial ECM, as part of the stem cell niche to ensure optimal stem cell regenerative capacity. Loss of *Adamts18* alters the stem cell niche and decreases mammary epithelial regenerative potential as its essential ECM modulatory function is abrogated.

The precise nature of the BM and interstitial ECM changes that alter signaling remain to be determined. Numerous factors, such as tissue stiffness and growth factor availability, directly or indirectly controlled by Adamts18 may be critical. The observed changes in the abundance of collagen I, collagen IV, laminin, fibronectin, and glycoproteins, like collagen XVIII, may be secondary to the reduced fibronectin clearance but Adamts18 may also be directly involved in their processing; other family members have glycoprotein substrates^[@CR14]^.

Increased laminin expression was also observed in *Adamts18*^*−/**−*^ adipose tissue^[@CR52]^ and embryonic brains^[@CR53]^ with effects on early adipocyte differentiation and spine and synapse formation. A detailed analysis of kidney and lung development in *WT* and *Adamts18*^*−/**−*^ mice revealed that expression of the enzyme by branching tips is impor