BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models

John Maringa Githaka, Namita Tripathi, Raven Kirschenman, Namrata Patel, Vrajesh Pandya, David A. Kramer, Rachel Montpetit, Lin Fu Zhu, Nahum Sonenberg, Richard P. Fahlman, Nika N. Danial, D. Alan Underhill and Ing Swie Goping ()
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John Maringa Githaka: University of Alberta
Namita Tripathi: University of Alberta
Raven Kirschenman: University of Alberta
Namrata Patel: University of Alberta
Vrajesh Pandya: University of Alberta
David A. Kramer: University of Alberta
Rachel Montpetit: University of Alberta
Lin Fu Zhu: University of Alberta
Nahum Sonenberg: McGill University
Richard P. Fahlman: University of Alberta
Nika N. Danial: Dana-Farber Cancer Institute
D. Alan Underhill: University of Alberta
Ing Swie Goping: University of Alberta

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Elucidation of non-canonical protein functions can identify novel tissue homeostasis pathways. Herein, we describe a role for the Bcl-2 family member BAD in postnatal mammary gland morphogenesis. In Bad3SA knock-in mice, where BAD cannot undergo phosphorylation at 3 key serine residues, pubertal gland development is delayed due to aberrant tubulogenesis of the ductal epithelium. Proteomic and RPPA analyses identify that BAD regulates focal adhesions and the mRNA translation repressor, 4E-BP1. These results suggest that BAD modulates localized translation that drives focal adhesion maturation and cell motility. Consistent with this, cells within Bad3SA organoids contain unstable protrusions with decreased compartmentalized mRNA translation and focal adhesions, and exhibit reduced cell migration and tubulogenesis. Critically, protrusion stability is rescued by 4E-BP1 depletion. Together our results confirm an unexpected role of BAD in controlling localized translation and cell migration during mammary gland development.

Date: 2021
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DOI: 10.1038/s41467-021-23269-8

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