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Annexin A1 is a polarity cue that directs planar mitotic spindle orientation during mammalian epithelial morphogenesis

ABSTRACT: Oriented cell divisions are critical for the formation and maintenance of structured epithelia. Proper mitotic spindle orientation relies on polarised anchoring of force generators to the cell cortex by the evolutionarily conserved Gαi-LGN-NuMA complex. However, the polarity cues that control cortical patterning of this ternary complex remain largely unknown in mammalian epithelia. Here we identify the membrane-associated protein Annexin A1 (ANXA1) as a novel interactor of LGN in mammary epithelial cells. ANXA1 acts independently of Gαi to instruct the accumulation of LGN and NuMA at the lateral cortex to ensure cortical anchoring of Dynein-Dynactin and astral microtubules and thereby planar alignment of the mitotic spindle. Loss of ANXA1 randomises mitotic spindle orientation, which in turn disrupts epithelial architecture and lumen formation in three-dimensional (3D) primary mammary organoids. Our findings establish ANXA1 as an upstream cortical cue that regulates LGN to direct planar cell divisions during mammalian epithelial morphogenesis.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Paul Skipp

LAB HEAD: Salah Elias

PROVIDER: PXD027452 | Pride | 2022-12-02

REPOSITORIES: Pride

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			Action	DRS
	Maria_150819_WT_001.mgf	Mgf
	Maria_150819_WT_001.msf.msf	Msf
	Maria_150819_WT_001.raw	Raw
	Maria_150819_ptk2_3_001.mgf	Mgf
	Maria_150819_ptk2_3_001.msf.msf	Msf

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Project description:Identify gene expression changes in the absence of Plk2 Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Comparison between Plk2 +/+ (n=3) and Plk2 -/- (n=3) mouse mammary epithelial cells

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Annexin A1 is a polarity cue that directs planar mitotic spindle orientation during mammalian epithelial morphogenesis

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