Multicellular Dynamics
Establishment of cell polarity and its relationship to signaling
Dra Sol Sotillos
Researcher
Summary
The interest of my laboratory is to understand how cell polarity influences cell behaviour and organism morphogenesis. All cells are polarized to a certain extent, which, depending on the cell type, results in an asymmetric distribution of molecules and organelles, creating different functional domains. There are polarity determinants involved in generating the different functional domains generate and maintain this polarity; cell trafficking proteins are involved in the movement of proteins and lipids between these functional domains; and cytoskeleton regulators, over which these functional domains are created and molecules are driven. Polarity is essential in morphogenesis, not only it controls cell homeostasis, but it also coordinates movements and shape changes required for the cell to integrate in the tissue and for the organogenesis to progress properly. Cell polarity control depends on the same signalling pathways regulating morphogenesis. However, this control is bidirectional as cell polarity is able to modulate signaling by influencing ligand secretion and receptor localization in the cell or by recruiting or sequestering signaling pathway components. My group has contributed to clarify how the cell determinant aPKC establishes and maintains cell polarity in Drosophila melanogaster, and to understand how cell polarity regulates JAK/STAT signaling in Drosophila’s epithelia. On the other hand, we have unravelled a new link between cell polarity and trafficking at the level of aPKC’s recycling by the Nuf-Rab11 complex, a process essential to maintain epithelia homeostasis.
Figure. Scheme showing the main cell polarity complexes. A) Drosophila embryonic epithelial cells showing polarized subcellular localization of the aPKC apical polarity determinant and the Scribble basolateral protein. B) In the WT aPKC localizes in apical whilst Scrib is basolateral. Overexpression of a dominant negative aPKC version (CAAXDN) affects cell polarity relocalizing Scribble to apical. C-D) Removal of aPKC’ interferes with cell polarity affecting the morphogenesis of structures as shown here for the Drosophila wing.
Recently we have described a new conserved function of Drosophila’s RhoGAP Cv-c and its human ortholog DLC3 for testis’ organization. We have demonstrated that Cv-c mutations similar to those on DLC3 linked to human testicular dysgenesis affect the testis organization preventing mesodermal cells to retain germ cells inside the testis.
Figure. Mesodermal cells in Drosophila and vertebrate testis are necessary for retaining the germ cells at the end of embryogenesis. Mesodermal cells signal and support germ cells (green) forming an extracellular cell matrix (white, left) surrounding the testis. In RhoGAP cv-c’ mutants this association is not maintained, the gonad breaks and the germ cells escape from the testis (green, right). Human DLC3, cv-c’ ortholog, is involved in testis formation during embryogenesis and its mutation results in 46X,Y dysgenesis.
Our current line of work combines molecular and cellular biology technics with Drosophila melanogaster genetics to: on the one hand, study the connexion between cell trafficking with the establishment and maintenance of cell polarity; and, on the other hand, decipher how cell polarity regulates organogenesis.
Five relevant publications
Lab members & Collaborators
Lab members
Associated Investigator:
Dr. Sol Sotillos
Collaborators
Dr. James Castelli-Gair Hombría (CABD, Sevilla)
Dra. Sonsoles Campuzano (CBMSO, Madrid)
Dra. Marta Llimargas (IBMB, Barcelona)
Dr. Jorge Moscat (Genome Research Institute, Cincinnati, USA)
Dra. María Teresa Díaz-Meco (Genome Research Institute, Cincinnati, USA)
Dr. José Felix de Celis (CBMSO, Madrid)
Dr. Michael Krahn (Institute for Molecular and Cellular Anatomy, Regensburg, Germany)
Dr. Juan Ramón Martínez Morales (CABD, Sevilla)
Full publication list
PUBLICATIONS
(Research papers)
(1) Hematopoietic cell-type-dependent regulation of leukocyte integrin functional activity: CD11b and CD11c expression inhibits LFA-1-dependent aggregation of differentiated U937 cells.
Nueda A, López-Rodríguez C, Rubio MA, Sotillos M, Postigo A, del Pozo MA, Vega MA, Corbí AL. Cell Immunol. 1995 Sep;164(2):163-9.
doi: 10.1006/cimm.1995.1157. PMID: 7656323
(2) Monocyte activation: rapid induction of alpha 1/beta 1 (VLA-1) integrin expression by lipopolysaccharide and interferon-gamma.
Rubio MA, Sotillos M, Jochems G, Alvarez V, Corbí AL. Eur J Immunol. 1995 Sep;25(9):2701-5.
doi: 10.1002/eji.1830250945. PMID: 7589148
(3) The metalloprotease-disintegrin Kuzbanian participates in Notch activation during growth and patterning of Drosophila imaginal discs.
Sotillos S, Roch F, Campuzano S. Development. 1997 Dec;124(23):4769-79.
doi: 10.1242/dev.124.23.4769. PMID: 9428413
(4) DRacGAP, a novel Drosophila gene, inhibits EGFR/Ras signalling in the developing imaginal wing disc.
Sotillos S, Campuzano S. Development. 2000 Dec;127(24):5427-38.
doi: 10.1242/dev.127.24.5427. PMID: 11076763
(5) DaPKC-dependent phosphorylation of Crumbs is required for epithelial cell polarity in Drosophila.
Sotillos S, Díaz-Meco MT, Caminero E, Moscat J, Campuzano S. J Cell Biol. 2004 Aug 16;166(4):549-57.
doi: 10.1083/jcb.200311031. Epub 2004 Aug 9. PMID: 15302858
(6) Interactions between the Notch, EGFR, and decapentaplegic signaling pathways regulate vein differentiation during Drosophila pupal wing development.
Sotillos S, De Celis JF. Dev Dyn. 2005 Mar;232(3):738-52.
doi: 10.1002/dvdy.20270. PMID: 15704120
(7) Regulation of decapentaplegic expression during Drosophila wing veins pupal development.
Sotillos S, de Celis JF. Mech Dev. 2006 Mar;123(3):241-51.
doi: 10.1016/j.mod.2005.12.002. Epub 2006 Jan 18. PMID: 16423512
(8) Compartmentalisation of Rho regulators directs cell invagination during tissue morphogenesis.
Simões S, Denholm B, Azevedo D, Sotillos S, Martin P, Skaer H, Hombría JC, Jacinto A. Development. 2006 Nov;133(21):4257-67.
doi: 10.1242/dev.02588. Epub 2006 Oct 4. PMID: 17021037
(9) Coordinated control of cell adhesion, polarity, and cytoskeleton underlies Hox-induced organogenesis in Drosophila.
Lovegrove B, Simões S, Rivas ML, Sotillos S, Johnson K, Knust E, Jacinto A, Hombría JC. Curr Biol. 2006 Nov 21;16(22):2206-16.
doi: 10.1016/j.cub.2006.09.029. PMID: 17113384
(10) Polarized subcellular localization of Jak/STAT components is required for efficient signaling.
Sotillos S, Díaz-Meco MT, Moscat J, Castelli-Gair Hombría J. Curr Biol. 2008 Apr 22;18(8):624-9.
doi: 10.1016/j.cub.2008.03.055. PMID: 18424141
(11) An efficient approach to isolate STAT regulated enhancers uncovers STAT92E fundamental role in Drosophila tracheal development.
Sotillos S, Espinosa-Vázquez JM, Foglia F, Hu N, Hombría JC. Dev Biol. 2010 Apr 15;340(2):571-82.
doi: 10.1016/j.ydbio.2010.02.015. Epub 2010 Feb 18. PMID: 20171201.
(12) Regulated Crb accumulation controls apical constriction and invagination in Drosophila tracheal cells.
Letizia A, Sotillos S, Campuzano S, Llimargas M. J Cell Sci. 2011 Jan 15;124(Pt 2):240-51.
doi: 10.1242/jcs.073601. Epub 2010 Dec 15. PMID: 21172808.
(13) Forces shaping a Hox morphogenetic gene network.
Sotillos S, Aguilar M, Hombría JC. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4303-8.
doi: 10.1073/pnas.1212970110. Epub 2013 Feb 25. PMID: 23440219.
(14) Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells.
Sotillos S*, Krahn M, Espinosa-Vázquez JM, Hombría JC. Development. 2013 Apr;140(7):1507-16.
doi: 10.1242/dev.092320. Epub 2013 Mar 5. PMID: 23462467.
(15) Common origin of insect trachea and endocrine organs from a segmentally repeated precursor.
Sánchez-Higueras C, Sotillos S, Castelli-Gair Hombría J. Curr Biol. 2014 Jan 6;24(1):76-81.
doi: 10.1016/j.cub.2013.11.010. Epub 2013 Dec 12. PMID: 24332544.
(16) Nuclear fallout provides a new link between aPKC and polarized cell trafficking.
Calero-Cuenca FJ, Espinosa-Vázquez JM, Reina-Campos M, Díaz-Meco MT, Moscat J, Sotillos S*. BMC Biol. 2016 Apr 18;14:32.
doi: 10.1186/s12915-016-0253-6. PMID: 27089924.
(17) Nuf and Rip11 requirement for polarity determinant recycling during Drosophila development.
Calero-Cuenca FJ, Sotillos S. Small GTPases. 2018 Jul 4;9(4):352-359.
doi: 10.1080/21541248.2016.1235386. Epub 2016 Nov 1. PMID: 27687567.
(18) Functional analysis of the Drosophila RhoGAP Cv-c protein and its equivalence to the human DLC3 and DLC1 proteins.
Sotillos S*, Aguilar-Aragon M, Hombría JC. Sci Rep. 2018 Mar 15;8(1):4601.
doi: 10.1038/s41598-018-22794-9. PMID: 29545526.
(19) Scutoids are a geometrical solution to three-dimensional packing of epithelia.
Gómez-Gálvez P, Vicente-Munuera P, Tagua A, Forja C, Castro AM, Letrán M, Valencia-Expósito A, Grima C, Bermúdez-Gallardo M, Serrano-Pérez-Higueras Ó, Cavodeassi F, Sotillos S, Martín-Bermudo MD, Márquez A, Buceta J, Escudero LM. Nat Commun. 2018 Jul 27;9(1):2960.
doi: 10.1038/s41467-018-05376-1. PMID: 30054479.
(20) A conserved function of Human DLC3 and Drosophila Cv-c in testis development.
Sotillos S*, von der Decken I, Domenech Mercadé I, Srinivasan S, Sirokha D, Livshits L, Vanni S, Nef S, Biason-Lauber A, Rodríguez Gutiérrez D, Castelli-Gair Hombría J. Elife. 2022 Nov 3;11:e82343.
doi: 10.7554/eLife.82343. PMID: 36326091.
* Corresponding author.
(Reviews)
(R1) JAK/STAT signalling: STAT cannot play with Ken and Barbie.
Hombría JC, Sotillos S. Curr Biol. 2006 Feb 7;16(3):R98-100.
doi: 10.1016/j.cub.2006.01.021. PMID: 16461274
(R2) Disclosing JAK/STAT links to cell adhesion and cell polarity.
Hombría JC, Sotillos S. Semin Cell Dev Biol. 2008 Aug;19(4):370-8.
doi: 10.1016/j.semcdb.2008.06.002. Epub 2008 Jun 11. PMID: 18590829
(R3) Genetic control of morphogenesis – Hox induced organogenesis of the posterior spiracles.
Castelli Gair Hombría J, Rivas ML, Sotillos S. Int J Dev Biol. 2009;53(8-10):1349-58. doi: 10.1387/ijdb.072421jc. PMID: 19247941
(R4) Evo-Devo: When Four Became Two Plus Two.
Hombría JC, Sotillos S. Curr Biol. 2020 Jun 8;30(11):R655-R657.
doi: 10.1016/j.cub.2020.04.022. PMID: 32516617
(Book chapters)
(C1) S. Sotillos y S. Campuzano. Role of achaete-scute complex genes in the development of the adult peripherial nervous system of Drosophila melanogaster In : “Key Experiments in Practical Developmental Biology” Marí-Beffa, M. and J. Knight (eds.) pp:255-268. (ISBN: 0521833159). Cambridge University
Press. New York.