Identification of Annexin A1 as a novel regulator of oriented cell divisions in mammary epithelial cell

Abstract

Oriented cell divisions (OCDs) represent a fundamental mechanism for tissue morphogenesis, repair and differentiation where the mitotic spindle is oriented along a specific polarity axis. Early research identified the evolutionarily conserved Gαi/LGN/NuMA ternary complex that mediates orientation of the mitotic spindle by being restricted to specific cortical regions. The mechanisms that control the recruitment of these proteins to the cortex remain unfolding, particularly in epithelial systems such as the mammary gland. The mammary gland represents a unique organ that develops predominantly after birth where postnatal morphogenesis of the mammary gland drives dramatic tissue turnover and remodelling. Thus, differentiation and proliferation are constantly balanced to allow normal mammary gland development and homeostasis. How mammary epithelial cells regulate mitotic spindle orientation, hence OCDs, to accompany the rapid and constant tissue turnover is not well understood. This study aimed to identify novel factors that regulate the LGN-mediated spindle orientation machinery and determine how their dysregulation affects OCDs in mammary epithelial cells. By combining co-immunoprecipitation with mass spectrometry, the LGN interactome at the cell cortex of mitotic mammary epithelial cells was characterised and the membrane-associated protein Annexin A1 (ANXA1) was identified as a novel partner of LGN. Confocal and time-lapse microscopy demonstrated a critical role of ANXA1 in regulating the position and planar orientation of the mitotic spindle by instructing the accumulation and restriction of the LGN complex at the lateral cortex. Moreover, loss of ANXA1 leads to mitotic spindle misassembly and chromosome segregation defects, affecting the dynamics and progression of mitosis. Collectively the present study identified ANXA1 as a novel intrinsic cue of OCDs in mammary epithelial cells. Given increasing evidence of a link between OCD and tumorigenesis, this work is not only important for advancing our understanding of normal epithelial biology but also elucidating how imbalance of OCDs can contribute to the abnormal cell behaviour observed in cancer.

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Identifiers

ORCID for Salah Elias: orcid.org/0000-0003-1005-438X

ORCID for Keith T Jones: orcid.org/0000-0002-0294-0851

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