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Going vertical: functional role and working principles of the protein Inscuteable in asymmetric cell divisions

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Abstract

Coordinating mitotic spindle dynamics with cortical polarity is essential for stem cell asymmetric divisions. Over the years, the protein Inscuteable (Insc) has emerged as a key element determining the spindle orientation in asymmetric mitoses. Its overexpression increases differentiative divisions in systems as diverse as mouse keratinocytes and radial glial cells. To date, the molecular explanation to account for this phenotype envisioned Insc as an adaptor molecule bridging between the polarity proteins Par3:Par6:aPKC and the spindle pulling machines assembled on NuMA:LGN:Gαi. However, recent biochemical and structural data revealed that Insc and NuMA are competitive interactors of LGN, challenging the simplistic idea of a single apical macromolecular complex, and demanding a revision of the actual working principles of Insc.

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References

  1. Kraut R, Campos-Ortega JA (1996) Inscuteable, a neural precursor gene of Drosophila, encodes a candidate for a cytoskeleton adaptor protein. Dev Biol 174:65–81

    Article  PubMed  CAS  Google Scholar 

  2. Kraut R, Chia W, Jan LY, Jan YN, Knoblich JA (1996) Role of Inscuteable in orienting asymmetric cell divisions in Drosophila. Nature 383:50–55

    Article  PubMed  CAS  Google Scholar 

  3. Neumuller RA, Knoblich JA (2009) Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes Dev 23:2675–2699

    Article  PubMed  Google Scholar 

  4. Schober M, Schaefer M, Knoblich JA (1999) Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila neuroblasts. Nature 402:548–551

    Article  PubMed  CAS  Google Scholar 

  5. Wodarz A, Ramrath A, Kuchinke U, Knust E (1999) Bazooka provides an apical cue for Inscuteable localization in Drosophila neuroblasts. Nature 402:544–547

    Article  PubMed  CAS  Google Scholar 

  6. Yu F, Morin X, Cai Y, Yang X, Chia W (2000) Analysis of partner of inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in inscuteable apical localization. Cell 100:399–409

    Article  PubMed  CAS  Google Scholar 

  7. Parmentier, M.L., Woods, D., Greig, S., Phan, P.G., Radovic, A., Bryant, P., and O’Kane, C.J. (2000). Rapsynoid/partner of inscuteable controls asymmetric division of larval neuroblasts in Drosophila. J Neurosci 20, RC84

  8. Siegrist SE, Doe CQ (2005) Microtubule-induced Pins/Galphai cortical polarity in Drosophila neuroblasts. Cell 123:1323–1335

    Article  PubMed  CAS  Google Scholar 

  9. Li P, Yang X, Wasser M, Cai Y, Chia W (1997) Inscuteable and Staufen mediate asymmetric localization and segregation of prospero RNA during Drosophila neuroblast cell divisions. Cell 90:437–447

    Article  PubMed  CAS  Google Scholar 

  10. Vessey JP, Amadei G, Burns SE, Kiebler MA, Kaplan DR, Miller FD (2012) An asymmetrically localized staufen2-dependent RNA complex regulates maintenance of Mammalian neural stem cells. Cell Stem Cell 11:517–528

    Article  PubMed  CAS  Google Scholar 

  11. Konno D, Shioi G, Shitamukai A, Mori A, Kiyonari H, Miyata T, Matsuzaki F (2008) Neuroepithelial progenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis. Nat Cell Biol 10:93–101

    Article  PubMed  CAS  Google Scholar 

  12. Postiglione MP, Juschke C, Xie Y, Haas GA, Charalambous C, Knoblich JA (2011) Mouse inscuteable induces apical-basal spindle orientation to facilitate intermediate progenitor generation in the developing neocortex. Neuron 72:269–284

    Article  PubMed  CAS  Google Scholar 

  13. Poulson ND, Lechler T (2010) Robust control of mitotic spindle orientation in the developing epidermis. J Cell Biol 191:915–922

    Article  PubMed  CAS  Google Scholar 

  14. Williams SE, Beronja S, Pasolli HA, Fuchs E (2011) Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470:353–358

    Article  PubMed  CAS  Google Scholar 

  15. Orgogozo V, Schweisguth F, Bellaiche Y (2001) Lineage, cell polarity and inscuteable function in the peripheral nervous system of the Drosophila embryo. Development 128:631–643

    PubMed  CAS  Google Scholar 

  16. Bellaiche Y, Radovic A, Woods DF, Hough CD, Parmentier ML, O’Kane CJ, Bryant PJ, Schweisguth F (2001) The Partner of Inscuteable/Discs-large complex is required to establish planar polarity during asymmetric cell division in Drosophila. Cell 106:355–366

    Article  PubMed  CAS  Google Scholar 

  17. Egger B, Boone JQ, Stevens NR, Brand AH, Doe CQ (2007) Regulation of spindle orientation and neural stem cell fate in the Drosophila optic lobe. Neural Develop 2:1

    Article  Google Scholar 

  18. Katoh M (2003) Identification and characterization of human Inscuteable gene in silico. Int J Mol Med 11:111–116

    PubMed  CAS  Google Scholar 

  19. Lechler T, Fuchs E (2005) Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437:275–280

    Article  PubMed  CAS  Google Scholar 

  20. Zigman M, Cayouette M, Charalambous C, Schleiffer A, Hoeller O, Dunican D, McCudden CR, Firnberg N, Barres BA, Siderovski DP et al (2005) Mammalian inscuteable regulates spindle orientation and cell fate in the developing retina. Neuron 48:539–545

    Article  PubMed  CAS  Google Scholar 

  21. Kotak S, Busso C, Gonczy P (2012) Cortical dynein is critical for proper spindle positioning in human cells. J Cell Biol 199:97–110

    Article  PubMed  CAS  Google Scholar 

  22. Peyre E, Jaouen F, Saadaoui M, Haren L, Merdes A, Durbec P, Morin X (2011) A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells. J Cell Biol 193:141–154

    Article  PubMed  CAS  Google Scholar 

  23. Kosodo Y, Roper K, Haubensak W, Marzesco AM, Corbeil D, Huttner WB (2004) Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J 23:2314–2324

    Article  PubMed  CAS  Google Scholar 

  24. Marthiens V, ffrench-Constant C (2009) Adherens junction domains are split by asymmetric division of embryonic neural stem cells. EMBO Rep 10:515–520

    Article  PubMed  CAS  Google Scholar 

  25. El-Hashash AH, Warburton D (2011) Cell polarity and spindle orientation in the distal epithelium of embryonic lung. Dev Dyn 240:441–445

    Article  PubMed  Google Scholar 

  26. Ben-Yair R, Kahane N, Kalcheim C (2011) LGN-dependent orientation of cell divisions in the dermomyotome controls lineage segregation into muscle and dermis. Development 138:4155–4166

    Article  PubMed  CAS  Google Scholar 

  27. Tio M, Zavortink M, Yang X, Chia W (1999) A functional analysis of inscuteable and its roles during Drosophila asymmetric cell divisions. J Cell Sci 112(Pt 10):1541–1551

    PubMed  CAS  Google Scholar 

  28. Knoblich JA, Jan LY, Jan YN (1999) Deletion analysis of the Drosophila Inscuteable protein reveals domains for cortical localization and asymmetric localization. Curr Biol 9:155–158

    Article  PubMed  CAS  Google Scholar 

  29. Yu F, Morin X, Kaushik R, Bahri S, Yang X, Chia W (2003) A mouse homologue of Drosophila pins can asymmetrically localize and substitute for pins function in Drosophila neuroblasts. J Cell Sci 116:887–896

    Article  PubMed  CAS  Google Scholar 

  30. Culurgioni S, Alfieri A, Pendolino V, Laddomada F, Mapelli M (2011) Inscuteable and NuMA proteins bind competitively to Leu-Gly-Asn repeat-enriched protein (LGN) during asymmetric cell divisions. Proc Natl Acad Sci USA 108:20998–21003

    Article  PubMed  CAS  Google Scholar 

  31. Yuzawa S, Kamakura S, Iwakiri Y, Hayase J, Sumimoto H (2011) Structural basis for interaction between the conserved cell polarity proteins Inscuteable and Leu-Gly-Asn repeat-enriched protein (LGN). Proc Natl Acad Sci USA 108:19210–19215

    Article  PubMed  CAS  Google Scholar 

  32. Zhu J, Wen W, Zheng Z, Shang Y, Wei Z, Xiao Z, Pan Z, Du Q, Wang W, Zhang M (2011) LGN/mInsc and LGN/NuMA Complex structures suggest distinct functions in asymmetric cell division for the Par3/mInsc/LGN and Galphai/LGN/NuMA Pathways. Mol Cell 43:418–431

    Article  PubMed  CAS  Google Scholar 

  33. Kiyomitsu, T., Cheeseman, I.M. (2011). Chromosome- and spindle-pole-derived signals generate an intrinsic code for spindle position and orientation. Nat Cell Biol 14:311–317

    Google Scholar 

  34. Izumi Y, Ohta N, Hisata K, Raabe T, Matsuzaki F (2006) Drosophila Pins-binding protein Mud regulates spindle-polarity coupling and centrosome organization. Nat Cell Biol 8:586–593

    Article  PubMed  CAS  Google Scholar 

  35. Bowman SK, Neumuller RA, Novatchkova M, Du Q, Knoblich JA (2006) The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division. Dev Cell 10:731–742

    Article  PubMed  CAS  Google Scholar 

  36. Siller KH, Cabernard C, Doe CQ (2006) The NuMA-related Mud protein binds Pins and regulates spindle orientation in Drosophila neuroblasts. Nat Cell Biol 8:594–600

    Article  PubMed  CAS  Google Scholar 

  37. Mapelli M, Gonzalez C (2012) On the inscrutable role of Inscuteable: structural basis and functional implications for the competitive binding of NuMA and Inscuteable to LGN. Open Biol 2:120102

    Article  PubMed  Google Scholar 

  38. Mauser JF, Prehoda KE (2012) Inscuteable regulates the Pins-Mud spindle orientation pathway. PLoS ONE 7:e29611

    Article  PubMed  CAS  Google Scholar 

  39. Johnston CA, Hirono K, Prehoda KE, Doe CQ (2009) Identification of an Aurora-A/PinsLINKER/Dlg spindle orientation pathway using induced cell polarity in S2 cells. Cell 138:1150–1163

    Article  PubMed  CAS  Google Scholar 

  40. Hao Y, Du Q, Chen X, Zheng Z, Balsbaugh JL, Maitra S, Shabanowitz J, Hunt DF, Macara IG (2010) Par3 controls epithelial spindle orientation by aPKC-mediated phosphorylation of apical Pins. Curr Biol 20:1809–1818

    Article  PubMed  CAS  Google Scholar 

  41. Matsumura S, Hamasaki M, Yamamoto T, Ebisuya M, Sato M, Nishida E, Toyoshima F (2011) ABL1 regulates spindle orientation in adherent cells and mammalian skin. Nat Commun 3:626

    Article  Google Scholar 

  42. Wang H, Cai Y, Chia W, Yang X (2006) Drosophila homologs of mammalian TNF/TNFR-related molecules regulate segregation of Miranda/Prospero in neuroblasts. EMBO J 25(24):5783–5793

    Google Scholar 

  43. Udolph G, Rath P, Tio M, Toh J, Fang W, Pandey R, Technau GM, Chia W (2009) On the roles of Notch, Delta, kuzbanian, and inscuteable during the development of Drosophila embryonic neuroblast lineages. Dev Biol 336:156–168

    Google Scholar 

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Acknowledgments

We are grateful to members of the Mapelli group and to Thomas Vaccari for critical reading of the manuscript. Mapelli’s laboratory is funded by the Italian Association for Cancer Research (AIRC) and the Italian Ministry of Health; S.C. is a FIRC postdoctoral fellow.

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Correspondence to Marina Mapelli.

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Culurgioni, S., Mapelli, M. Going vertical: functional role and working principles of the protein Inscuteable in asymmetric cell divisions. Cell. Mol. Life Sci. 70, 4039–4046 (2013). https://doi.org/10.1007/s00018-013-1319-z

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