Cilia Regulation and Disease

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Susana Lopes

Principal Investigator

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Location:

CEDOC
Campus Sant'Ana
Pólo de Investigação, NMS, UNL
Rua do Instituto Bacteriológico, nº 5
1150-082 Lisboa, Portugal

Phone: (+351) 218 803 101
E-mail: susana.lopes(at)nms.unl.pt

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Main interests

Cilia length and motility regulation
Cilia are cellular organelles that protrude from almost every cell membrane. Cilia can be motile or immotile and can appear isolated or in bundles per cell. All types of cilia are thought to have signaling properties. Important signaling pathways during animal development and disease have been related to cilia, such as the Hedgehog, FGF and Notch signaling pathways. When cilia have defective length Hedgehog signaling is abnormal. On the other hand, Notch and FGF signaling defects trigger ciliary length and motility problems. We study cilia length and motility regulation in order to understand ciliopathies. We use the vertebrate zebrafish embryo because it has many ciliated organs with all cilia types and offers excellent imaging and genetic advantages.

Ciliopathies
Cilia have acquired major biomedical relevance due to the disclosure of many different diseases as ciliopathies i.e. diseases that have a ciliary origin. Ciliary protein defects underlie several human syndromes, such as Bardet-Biedl, Alstrom, Joubert, Senior-Løken, Meckel-Gruber, and Oral Facial Digit syndromes, that involve different conjugations of conditions such as polycystic kidney disease, retinal degeneration, anosmia, polydactyly, or organ situs reversal. Several of these syndromes show features not obviously related to cilia, including obesity and mental retardation. Human syndromes such as Kartagener were already identified as ciliopathies affecting motile cilia but many others such as Jeune asphyxiating thoracic dystrophy were not known as ciliopathies and have only recently been allocated to defects in primary cilia signaling. Ciliopathies affect many cell types and organs including kidney, liver, pancreas, heart, lungs, nose, ears, eyes and brain.

Research Areas

• Cilia length regulation.
• Cilia motility: beat frequency and pattern
• Cilia generated fluid flow dynamics within embryonic organs
• Ciliary mechano-sensory versus chemo-sensory signaling pathways

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AWARD from Sociedade Portuguesa de Nefrologia

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Project: Sphingolipid Signaling and CFTR stimulation in Autosomal Dominant Polycystic Kidney Disease

Team: Mónica Roxo-Rosa (PI), Susana Lopes, Bárbara Tavares and Joaquim Calado (ToxOmics)

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Projects

1- Research on Delta-Notch Signaling
We have found that this signaling pathway is important for ciliary length regulation. We are investigating how is DeltaD linked to ciliogenesis and its impact on left-right development. This project is an ongoing screen and we have now identified many interesting genes that are differentially expressed in zebrafish wild-type embryos and deltaD homozygous mutants. Our aim is to understand what are the genes downstream of the Delta-Notch signaling that can rescue cilia length and motility. We have found new genes and new mechanisms involved in these two processes.

2- Research on Arl13b and Cilia Length Regulation
This collaborative project with Barral’s group from CEDOC aims to investigate the role of Arl13b in cilia length control. We are trying to find out what are the effectors of Arl13b in the zebrafish motile cilia. This protein is highly expressed along cilia but its function there is not well understood.

3- Research on Left-Right Development
We have recently started to study what are the signaling events that are triggered by the ciliary Pkd2 calcium channel in the left-right organizer. Our aim is to find downstream signaling pathways that interpret the nodal flow and translate it into left-right cues that determine organ laterality during development. This project (FCT-ANR /BEX-BID/0153/2012) is a Franco-Portuguese collaboration with Julien Vermot at the IGBMC, Strasbourg.

4- Research on Zebrafish Nephrotoxicity
This collaborative project with Monteiro’s Pharmacology group from CEDOC is a pilot study to determine if the zebrafish kidney is a good model to study toxicity triggered by anti-retroviral treatments. The aim is to find ways to reduce nephrotoxicity. Because the kidney is a ciliated organ, we are also investigating how kidney cilia respond to such toxicity and whether cilia can have an important role in reducing toxicity.

Selected Publications
  • Smith Dj, Montenegro-Johnson T, Lopes S.S. (2014) Organized chaos in Kupffer's vesicle: How a heterogeneous structure achieves consistent left-right patterning. May-Jun;4(3):119-25. Bioarchitecture doi: 10.4161/19490992.2014.956593.
  • Cristina Casalou, Cecília Seixas, Ana Portelinha, Petra Pintado, Mafalda Barros, José S Ramalho, Susana S Lopes, Duarte C Barral (2014) Arl13b and the non-muscle myosin heavy chain IIA are required for circular dorsal ruffle formation and cell migration. Journal of cell science, jcs. 143446
  • Tavares B, Santos Lopes S. (2013) The Importance of Zebrafish in Biomedical Research. Acta Med Port., 26(5):583-592. Epub 2013 Oct 31.
  • Lourenço R, Lopes SS, Saúde L. Left-right function of dmrt2 genes is not conserved between zebrafish and mouse. PLoS One. 2010 Dec 28;5(12):e14438. PMID:21203428
  • Lopes SS, Lourenço R, Pacheco L, Moreno N, Kreiling J, Saúde L. Notch signalling regulates left-right asymmetry through ciliary length control. Development. 2010 Nov;137(21):3625-32. Epub 2010 Sep 28. PMID: 20876649
  • Rocha SF, Lopes SS, Gossler A, Henrique D. Dll1 and Dll4 function sequentially in the retina and pV2 domain of the spinal cord to regulate neurogenesis and create cell diversity. Dev Biol. 2009 Apr 1;328(1):54-65. Epub 2009 Jan 14. PMID: 19389377
  • Lopes SS, Yang X, Müller J, Carney TJ, McAdow AR, Rauch GJ, Jacoby AS, Hurst LD, Delfino-Machín M, Haffter P, Geisler R, Johnson SL, Ward A, Kelsh RN. Leukocyte tyrosine kinase functions in pigment cell development. PLoS Genet. 2008 Mar 7;4(3):e1000026. PMID:18369445
  • Dutton KA, Pauliny A, Lopes SS, Elworthy S, Carney TJ, Rauch J, Geisler R, Haffter P, Kelsh RN. Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. Development. 2001 Nov;128(21):4113-25. PMID: 11684650
  • Parichy DM, Mellgren EM, Rawls JF, Lopes SS, Kelsh RN, Johnson SL. Mutational analysis of endothelin receptor b1 (rose) during neural crest and pigment pattern development in the zebrafish Danio rerio. Dev Biol. 2000 Nov 15;227(2):294-306. PMID: 11071756

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Ongoing collaborations

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- Duarte Barral CEDOC - Chronic Diseases Research Centre, Oeiras
- Emília Monteiro CEDOC - Chronic Diseases Research Centre, Lisbon
- Adan Guerrero Instituto Gulbenkian de Ciência, Oeiras
- Leonor Saúde IMM - Instituto Medicina Molecular, Lisbon
- David Smith University of Birmingham, School of Mathematics, Birmingham, UK
- Julien Vermot IGBMC – Institute de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
- Christopher Westlake CCR - Center for Cancer Research, Bethesda, US
 
 
 

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Team photos

lab day out Sintra1

1st retreat Algarve

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We welcome spontaneous Applications from posdocs with strong experience in
molecular biology.
 
Contact: susana.lopes(at)nms.unl.pt