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

Author

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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
    University of Alberta)

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.

Suggested Citation

  • 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 & , 2021. "BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23269-8
    DOI: 10.1038/s41467-021-23269-8
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