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    • We previously identified a role for

    2018-10-26

    We previously identified a role for the transcription factor Gata3 in prostate cancer (Nguyen et al., 2013). GATA3 expression is lost during cancer progression in both mouse and human prostates. In Pten-deficient mice, acute inactivation of Gata3 accelerates prostate cancer progression, while its sustained expression delays the transition to carcinoma (Nguyen et al., 2013). Gata3 is also important for the specification and maintenance of many epithelial tissues including the epidermis and mammary gland, and is a recognized tumor suppressor in breast cancer (Asselin-Labat et al., 2007; Dydensborg et al., 2009; Kaufman et al., 2003). However, the role that Gata3 plays during prostate development and in the generation and maintenance of epithelial polarity and homeostasis is poorly understood. Here, we show that Gata3 regulates epithelial progenitor cell division via atypical protein kinase C (PRKCZ) to control lineage commitment during prostate development. This function of Gata3 is achieved through precise regulation of spindle orientation in progenitor cells, disruption of which is sufficient to induce epithelial cell lineage and morphological defects.
    Results
    Discussion Basal prostate epithelial p2x7 divide either symmetrically to expand the basal progenitor cell pool, or asymmetrically to generate double-positive intermediate progenitor cells or differentiated luminal cells (Ousset et al., 2012; Wang et al., 2013; Wuidart et al., 2016). However, the molecular determinants underlying this process and the consequences of altering spindle orientation in the prostate are currently unknown. In this report we show that loss of Gata3 leads to tissue hyperplasia by accumulation of a poorly polarized cell layer at the interphase between the basal and luminal cells, largely composed of intermediate progenitor cells. This disruption in tissue architecture results from a defect in mitotic spindle orientation secondary to mislocalization of the polarity protein PRKCZ from PARD3/PARD6B. Accordingly, disruption of the PRKCZ-PARD6B interaction by ATM alone was sufficient to disrupt spindle orientation and lineage specification. Together, these results underscore the critical importance of regulating spindle orientation within progenitor cells to generate and maintain stable tissue architecture composed of stratified basal and luminal cell layers. The most striking phenotype observed in Gata3-deficient prostates is a complete randomization of the mitotic spindle in both basal and luminal cells. In other systems, orientation of the mitotic spindle is recognized as the primary endogenous mechanism to regulate symmetric versus asymmetric cell divisions and control the inheritance of cellular fates within the resulting daughter cells (Knoblich, 2010; Morin and Bellaiche, 2011; Neumuller and Knoblich, 2009). This developmental program and its regulatory machinery are largely conserved during evolution, but little is known of the role of spindle and polarity proteins during development and homeostasis (Pearson et al., 2011; Win and Acevedo-Duncan, 2008; Zhang et al., 2016). Evidence from lineage tracing analysis and measurements of the mitotic spindle during lineage specification strongly support the presence of bipotent basal progenitor cells able to expand the basal compartment via laterally oriented divisions, or generate differentiated luminal cells via apical-oriented divisions (Ousset et al., 2012; Wang et al., 2014). Generation of luminal cells is partially accomplished through the formation of intermediate progenitors with a “double-positive” (CK5+; CK8/18+) signature. In contrast, luminal cells appear to be strictly unipotent and only capable of planar-oriented divisions during development and homeostasis. Importantly, this differentiation process occurs in a highly regulated manner such that prostatic ducts maintain stratified and single-cell thick layers of basal and luminal cells following mitotic events. In Gata3-deficient embryos, mitotic spindle randomization does not overtly affect the basal progenitor pool or the polarity of differentiated non-proliferative cells lining the lumen. Instead, it affects the relative allocation of the different lineages by accumulation of intermediate progenitor cells at the interphase between the differentiated basal and luminal cell compartments. These progenitor cells, along with oblique and apical divisions of luminal cells, disrupt tissue architecture by generating a surplus of luminal cells. Although we cannot exclude the possibility that some double-positive cells arise from aberrant luminal cell divisions, the fact that we observe spindle randomization in basal cell progenitors indicates disruption of the normal specification process in those cells.