TY - JOUR
T1 - Mosaic loss of non-muscle myosin IIA and IIB is sufficient to induce mammary epithelial proliferation
AU - Nguyen-Ngoc, Kim Vy
AU - Silvestri, Vanesa L.
AU - Georgess, Dan
AU - Fairchild, Amanda N.
AU - Ewald, Andrew J.
N1 - Funding Information:
D.G. is funded by a postdoctoral fellowship grant from the Susan G. Komen for the Cure foundation (PDF15332336). A.J.E. received support for this project from the Commonwealth Foundation, the Breast Cancer Research Foundation/Pink Agenda (BCRF-16-048), a grant from the National Institutes of Health (National Cancer Institute) (U54 CA2101732), the Isaac and Lucille Hay Fellowship, and the Climb for Hope foundation. Deposited in PMC for release after 12 months.
Publisher Copyright:
© 2017.
PY - 2017
Y1 - 2017
N2 - 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 is therefore a plausible regulator of mammary morphogenesis. We tested the genetic requirement for NMIIA and NMIIB in mammary morphogenesis through deletion of the three NMII heavy chain-encoding genes (NMHCIIA, NMHCIIB and NMHCIIC; also known as MYH9, MYH10 and MYH14, respectively) that confer specificity to the complex. Surprisingly,mosaic loss, but not ubiquitous loss, of NMHCIIA and NMHCIIB induced high levels of proliferation in 3D culture. This phenotype was observed even when cells were cultured in basal medium, which does not support tissue level growth of wild-type epithelium. Mosaic loss of NMIIA and NMIIB combined with FGF signaling to induce hyperplasia. Mosaic analysis revealed that the cells that were null for both NMIIA and NMIIB, as well as wild-type cells, proliferated, indicating that the regulation of proliferation is both cell autonomous and non-autonomous within epithelial tissues. This phenotype appears to be mediated by cell-cell contact, as co-culture did not induce proliferation. Mosaic loss ofNMIIA and NMIIB also induced excess proliferation in vivo. Our data therefore reveal a role forNMIIA andNMIIB as negative regulators of proliferation in the mammary epithelium.
AB - 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 is therefore a plausible regulator of mammary morphogenesis. We tested the genetic requirement for NMIIA and NMIIB in mammary morphogenesis through deletion of the three NMII heavy chain-encoding genes (NMHCIIA, NMHCIIB and NMHCIIC; also known as MYH9, MYH10 and MYH14, respectively) that confer specificity to the complex. Surprisingly,mosaic loss, but not ubiquitous loss, of NMHCIIA and NMHCIIB induced high levels of proliferation in 3D culture. This phenotype was observed even when cells were cultured in basal medium, which does not support tissue level growth of wild-type epithelium. Mosaic loss of NMIIA and NMIIB combined with FGF signaling to induce hyperplasia. Mosaic analysis revealed that the cells that were null for both NMIIA and NMIIB, as well as wild-type cells, proliferated, indicating that the regulation of proliferation is both cell autonomous and non-autonomous within epithelial tissues. This phenotype appears to be mediated by cell-cell contact, as co-culture did not induce proliferation. Mosaic loss ofNMIIA and NMIIB also induced excess proliferation in vivo. Our data therefore reveal a role forNMIIA andNMIIB as negative regulators of proliferation in the mammary epithelium.
KW - 3D culture
KW - Cell proliferation
KW - Mammary epithelial organoid
KW - Non-muscle myosin IIA
KW - Non-muscle myosin IIB
KW - Tissue growth
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U2 - 10.1242/jcs.208546
DO - 10.1242/jcs.208546
M3 - Article
C2 - 28821574
AN - SCOPUS:85030552788
VL - 130
SP - 3213
EP - 3221
JO - The Quarterly journal of microscopical science
JF - The Quarterly journal of microscopical science
SN - 0021-9533
IS - 19
ER -