title: Lineage Specification from Prostate Progenitor Cells Requires Gata3-Dependent Mitotic Spindle Orientation.
abstract: During prostate development, basal and luminal cell lineages are generated through symmetric and asymmetric divisions of bipotent basal cells. However, the extent to which spindle orientation controls division symmetry or cell fate, and the upstream factors regulating this process, are still elusive. We report that GATA3 is expressed in both prostate basal progenitor and luminal cells and that loss of GATA3 leads to a mislocalization of PRKCZ, resulting in mitotic spindle randomization during progenitor cell division. Inherently proliferative intermediate progenitor cells accumulate, leading to an expansion of the luminal compartment. These defects ultimately result in a loss of tissue polarity and defective branching morphogenesis. We further show that disrupting the interaction between PRKCZ and PARD6B is sufficient to recapitulate the spindle and cell lineage phenotypes. Collectively, these results identify a critical role for GATA3 in prostate lineage specification, and further highlight the importance of regulating spindle orientation for hierarchical cell lineage organization.
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
authors.forename: Maxwell E R
authors.initials: MER
authors.lastname: Shafer
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada.
authors.forename: Alana H T
authors.initials: AHT
authors.lastname: Nguyen
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Tremblay
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Viala
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Béland
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Bertos
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Departments of Medicine and Oncology, McGill University, Montreal, QC H4A 3T2, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 415, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada. Electronic address: maxime.bouchard@mcgill.ca.
authors.forename: Maxime
authors.initials: M
authors.lastname: Bouchard
mesh_terms: D000818:Animals; D016764:Cell Polarity; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D008297:Male; D008810:Mice, Inbred C57BL; D011467:Prostate / Q000166:cytology / Q000254:growth & development* / Q000648:ultrastructure; D011493:Protein Kinase C / Q000032:analysis / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D050990:GATA3 Transcription Factor; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C494748:Gata3 protein, mouse
keywords: GATA3; atypical protein kinase C; aurothiomalate; cell polarity; epithelial stratification; lineage specification; par complex; prostate development; prostate progenitor cells; spindle orientation