Mosaic loss of non-muscle myosin IIA and IIB is sufficient to induce mammary epithelial proliferation

The mammary epithelium elaborates through hormonally-regulated changes in proliferation, migration, and differentiation. Non-muscle myosin II (NMII) functions at the interface between contractility, adhesion, and signal transduction. It was therefore a plausible regulator of mammary morphogenesis. We tested the genetic requirement for NMIIA and NMIIB through deletion of the myosin heavy chains (NMHC) that confer specificity to the complex. Surprisingly, mosaic loss, but not ubiquitous loss, of NMHCIIA and IIB induced high levels of proliferation in 3D culture. This phenotype was observed even in basal media conditions that do not support tissue level growth of wildtype epithelium. Mosaic loss of NMIIA and IIB combined with FGF signaling to induce hyperplasia. Mosaic analysis revealed that both NMIIA,B-null and wild-type cells proliferated, indicating that the regulation of proliferation is both cell autonomous and non-autonomous within epithelial tissues. This phenotype appears mediated by cell-cell contact, as co-culture did not induce proliferation. Mosaic loss of NMIIA and IIB also induced excess proliferation in vivo. Our data therefore reveal a role for NMIIA and NMIIB as negative regulators of proliferation in the mammary epithelium.