The Spindle Orientation Machinery Beyond Mitosis: When Cell Specialization Demands Polarization

Tadenev, Abigail L.D.; Tarchini, Basile

doi:10.1007/978-3-319-57127-0_9

Cited by 7 publications

(4 citation statements)

References 110 publications

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“…The GDI protein G protein signaling modulator 2 (GPSM2) is a conserved partner of GNAI during oriented cell division (6,7). In dividing cells, the cortical GPSM2-GNAI(GDP) polarity complex orients the mitotic spindle by recruiting effectors that exert force on astral microtubules (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

2022

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Inhibitory G proteins (GNAI/Gα i ) bind to the scaffold G protein signaling modulator 2 (GPSM2) to form a conserved polarity complex that regulates cytoskeleton organization. GPSM2 keeps GNAI in a guanosine diphosphate (GDP)-bound state, but how GPSM2-GNAI is generated or relates to heterotrimeric G protein signaling remains unclear. We find that RGS12, a GTPase-activating protein (GAP), is required to polarize GPSM2-GNAI at the hair cell apical membrane and to organize mechanosensory stereocilia in rows of graded heights. Accordingly, RGS12 and the guanine nucleotide exchange factor (GEF) DAPLE are asymmetrically co-enriched at the hair cell apical junction, and Rgs12 mouse mutants are deaf. GPSM2 and RGS12 share GoLoco motifs that stabilize GNAI(GDP), and GPSM2 outcompetes RGS12 to bind GNAI. Our results suggest that polarized GEF/GAP junctional activity might dissociate heterotrimeric G proteins, generating free GNAI(GDP) for GPSM2 at the adjacent apical membrane. GPSM2-GNAI(GDP), in turn, imparts asymmetry to the forming stereocilia to enable sensory function in hair cells.

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Section: Introductionmentioning

confidence: 99%

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

2022

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“…In Drosophila , the LGN ortholog Pins plays a key role in neuroblast stem cells, where it orients the mitotic spindle to promote the unequal inheritance of fate determinants that results in asymmetric daughter cell fates ( Bellaïche et al, 2001 ; Schaefer et al, 2000 ). The Par3/aPKC/Par6 polarity complex and Insc—among other proteins—facilitate membrane association of the LGN–NuMA–Gαi ternary complex, while downstream, the motor protein dynein mediates pulling forces on astral microtubules to reorient the spindle (reviewed in Bergstralh et al, 2013 ; di Pietro et al, 2016 ; Morin and Bellaïche, 2011 ; Tadenev and Tarchini, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Descovich

Lough

Jena

et al. 2023

eLife

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Oriented cell divisions balance self-renewal and differentiation in stratified epithelia such as the skin epidermis. During peak epidermal stratification, the distribution of division angles among basal keratinocyte progenitors is bimodal, with planar and perpendicular divisions driving symmetric and asymmetric daughter cell fates, respectively. An apically-restricted, evolutionarily-conserved spindle orientation complex that includes the scaffolding protein LGN/Pins/Gpsm2 plays a central role in promoting perpendicular divisions and stratification, but why only a subset of cell polarize LGN is not known. Here, we demonstrate that the LGN paralog, AGS3/Gpsm1, is a novel negative regulator of LGN, and inhibits perpendicular divisions. Static and ex vivo live imaging reveal that AGS3 overexpression displaces LGN from the apical cortex and increases planar orientations, while AGS3 loss prolongs cortical LGN localization and leads to a perpendicular orientation bias. Genetic epistasis experiments in double mutants confirm that AGS3 operates through LGN. Finally, clonal lineage tracing shows that LGN and AGS3 promote asymmetric and symmetric fates, respectively, while also influencing differentiation through delamination. Collectively, these studies shed new light into how spindle orientation influences epidermal stratification.

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“…In Drosophila , the LGN ortholog Pins plays a key role in neuroblast stem cells, where it orients the mitotic spindle to promote the unequal inheritance of fate determinants that results in asymmetric daughter cell fates (Bellaiche et al, 2001; Schaefer et al, 2000). The Par3/aPKC/Par6 polarity complex and Insc—among other proteins—facilitate membrane association of the LGN-NuMA-Gαi ternary complex, while downstream, the motor protein dynein mediates pulling forces on astral microtubules to reorient the spindle, (reviewed in Bergstralh, Haack, & St Johnston, 2013; di Pietro, Echard, & Morin, 2016; Morin & Bellaiche, 2011; Tadenev & Tarchini, 2017).…”

Section: Introductionmentioning

confidence: 99%

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Descovich

Lough

Jena

et al. 2022

Preprint

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Oriented cell divisions balance self-renewal and differentiation in stratified epithelia such as the skin epidermis. During peak epidermal stratification, the distribution of division angles among basal keratinocyte progenitors is bimodal, with planar and perpendicular divisions driving symmetric and asymmetric daughter cell fates, respectively. An apically-polarized, evolutionarily-conserved spindle orientation complex that includes the scaffolding protein LGN/Pins/Gpsm2 plays a central role in promoting perpendicular divisions and stratification, but little is known about the molecular regulation of planar divisions. Here, we demonstrate that the LGN paralog, AGS3/Gpsm1, is a novel negative regulator of LGN, and inhibits perpendicular divisions. Static and ex vivo live imaging reveal that AGS3 overexpression displaces LGN from the apical cortex and increases planar orientations, while AGS3 loss prolongs cortical LGN localization and leads to a perpendicular orientation bias. Genetic epistasis experiments in double mutants confirm that AGS3 operates through LGN. Finally, clonal lineage tracing shows that LGN and AGS3 promote asymmetric and symmetric fates, respectively, while also influencing differentiation through delamination. Collectively, these studies shed new light into how spindle orientation influences epidermal stratification.

show abstract

The Spindle Orientation Machinery Beyond Mitosis: When Cell Specialization Demands Polarization

Cited by 7 publications

References 110 publications

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

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