TY - JOUR
T1 - Patterned collagen fibers orient branching mammary epithelium through distinct signaling modules
AU - Brownfield, Douglas G.
AU - Venugopalan, Gautham
AU - Lo, Alvin
AU - Mori, Hidetoshi
AU - Tanner, Kandice
AU - Fletcher, Daniel A.
AU - Bissell, Mina J.
N1 - Funding Information:
This research was supported by grants from the US Department of Energy and the Office of Biological and Environmental Research (DE-AC02-05CH1123) to M.J.B.; by the National Cancer Institute (NCI) (R37CA064786, U54CA126552, U01CA143233, U54CA112970, and U54CA143836; Bay Area Physical Sciences–Oncology Center, University of California) to M.J.B. and D.G.B.; and by a US Department of Defense Innovator Award (W81XWH0810736) to M.J.B. The work of D.A.F. and G.V. was supported by the NCI and National Science Foundation. We are grateful to Saori Furuta as well as both the Bissell and Fletcher laboratories for discussion and critical reading of the manuscript. We thank Sanjay Kumar and Joanna MacKay for the image correlation MATLAB code.
PY - 2013/4/22
Y1 - 2013/4/22
N2 - For decades, the work of cell and developmental biologists has demonstrated the striking ability of the mesenchyme and the stroma to instruct epithelial form and function in the mammary gland [1-3], but the role of extracellular matrix (ECM) molecules in mammary pattern specification has not been elucidated. Here, we show that stromal collagen I (Col-I) fibers in the mammary fat pad are axially oriented prior to branching morphogenesis. Upon puberty, the branching epithelium orients along these fibers, thereby adopting a similar axial bias. To establish a causal relationship from Col-I fiber to epithelial orientation, we embedded mammary organoids within axially oriented Col-I fiber gels and observed dramatic epithelial co-orientation. Whereas a constitutively active form of Rac1, a molecule implicated in cell motility, prevented a directional epithelial response to Col-I fiber orientation, inhibition of the RhoA/Rho-associated kinase (ROCK) pathway did not. However, time-lapse studies revealed that, within randomly oriented Col-I matrices, the epithelium axially aligns fibers at branch sites via RhoA/ROCK-mediated contractions. Our data provide an explanation for how the stromal ECM encodes architectural cues for branch orientation as well as how the branching epithelium interprets and reinforces these cues through distinct signaling processes.
AB - For decades, the work of cell and developmental biologists has demonstrated the striking ability of the mesenchyme and the stroma to instruct epithelial form and function in the mammary gland [1-3], but the role of extracellular matrix (ECM) molecules in mammary pattern specification has not been elucidated. Here, we show that stromal collagen I (Col-I) fibers in the mammary fat pad are axially oriented prior to branching morphogenesis. Upon puberty, the branching epithelium orients along these fibers, thereby adopting a similar axial bias. To establish a causal relationship from Col-I fiber to epithelial orientation, we embedded mammary organoids within axially oriented Col-I fiber gels and observed dramatic epithelial co-orientation. Whereas a constitutively active form of Rac1, a molecule implicated in cell motility, prevented a directional epithelial response to Col-I fiber orientation, inhibition of the RhoA/Rho-associated kinase (ROCK) pathway did not. However, time-lapse studies revealed that, within randomly oriented Col-I matrices, the epithelium axially aligns fibers at branch sites via RhoA/ROCK-mediated contractions. Our data provide an explanation for how the stromal ECM encodes architectural cues for branch orientation as well as how the branching epithelium interprets and reinforces these cues through distinct signaling processes.
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U2 - 10.1016/j.cub.2013.03.032
DO - 10.1016/j.cub.2013.03.032
M3 - Article
C2 - 23562267
AN - SCOPUS:84876774048
SN - 0960-9822
VL - 23
SP - 703
EP - 709
JO - Current Biology
JF - Current Biology
IS - 8
ER -