Lineage Specification from Prostate Progenitor Cells Requires Gata3-Dependent Mitotic Spindle Orientation

Abstract

SummaryDuring 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.

GATA transcription factors in development and disease

“…As is the case for the mammary gland, GATA3 plays a key role in prostate development. However, in contrast to its luminal-restricted expression observed in the mammary gland, Gata3 is expressed in both basal and luminal lineages of the prostate (Shafer et al, 2017). Loss of Gata3 in the developing prostate (using Nkx3.1 Cre ) does not prevent luminal cell differentiation but causes an accumulation of intermediate progenitor cells associated with loss of polarity, tissue hyperplasia and defective branching morphogenesis (Fig.…”

“…6). These malformations stem from defects in lineage commitment through oriented cell division in progenitor cells (Shafer et al, 2017). In the adult prostate, Gata2 and Gata3 act redundantly, as only double knockouts (using Pb Cre ) show altered expression of AR and an expansion of the basal cell compartment (Xiao et al, 2016).…”

Regulation of stem/progenitor cell maintenance by BMP5 in prostate homeostasis and cancer initiation

“…Gata3 has previously been reported to play a role in prostate development ( Shafer et al, 2017 ) and in cancer progression ( Nguyen et al, 2013 ). Whether Gata3 also regulates adult prostate stem cell homeostasis remains unknown.…”

“…However, basal stem cells act as facultative stem cells by activating basal to luminal lineage conversion under various stress conditions ( Kwon et al, 2014 ; Toivanen et al, 2016 ). In contrast, basal stem cells are constitutively multipotent in the developing prostate, where they populate the luminal cell layer through asymmetric cell divisions ( Ousset et al, 2012 ; Shafer et al, 2017 ; Wang et al, 2014a ). In prostate cancer, basal and luminal stem cells can both act as tumor-initiating cells and are thought to contribute to tumor recurrence ( Choi et al, 2012 ; Goldstein et al, 2010 ; Wang et al, 2009 ; Wang et al, 2013 ; Zhao et al, 2018 ).…”

“…In recent years, GATA transcription factors have emerged as important regulators of prostate development and cancer ( Nguyen et al, 2013 ; Shafer et al, 2017 ; Xiao et al, 2016 ). During postnatal development, GATA3 is expressed in both basal and luminal cells and plays an important role in lineage specification and tissue organization ( Shafer et al, 2017 ). In cancer, nuclear loss of GATA3 is associated with the progression to castration-resistant prostate cancer (CRPC) and poor prognosis ( Nguyen et al, 2013 ).…”