We are interested in understanding the molecular mechanisms promoting organism development, survival and reproduction in unfavorable conditions. We expect to provide insights into the molecular mechanisms coordinating human organ growth and maturation during normal development and disease. To achieve these goals, we use a diverse set of techniques, from molecular and cell biology to fluorescence microscopy and several models, such as cultured cells and Drosophila melanogaster.
Coordination of growth and maturation time in animals
The aim of this project is to understand the molecular mechanisms underlying how organ growth and developmental timing are coordinated in animals both in normal conditions and when damage or abnormal growth of tissues occurs during development. Towards this objective, an integrative approach is being employed to study the evolution, biology and mechanism of action of Dilp8, the key insulin-like peptide coordinating growth and maturation time in Drosophila (Garelli et al., Science 2012; Colombani et al., Science 2012). Recent results have shown that Dilp8 acts via a subpopulation of CNS neurons expressing the relaxin receptor Lgr3, which is required to transduce the Dilp8 signal from the periphery to the endocrine gland controlling the onset of metamorphosis (Garelli et al., Nat Commun, 2015; Colombani et al., Curr Biol, 2015; Vallejo et al., Science, 2015). This points to an ancient role for neuronal relaxin receptors for sensing peripheral stress and promoting developmental stability. By elucidating how Dilp8 evolved and got integrated into a conserved growth and tissue-stress-sensing pathway, we expect to provide insights into the molecular mechanisms coordinating human organ growth and maturation during normal development and disease.
Repetitive-element activity and their role in aging and disease
Retrotransposable elements (REs) colonize genomes by copying themselves via an RNA-intermediate. REs are thus potential endogenous mutagens, against which their host organisms have evolved several repressive mechanisms to control their activities. Unfortunately, these control mechanisms somehow tend to fail as cells age. This phenomenon has been documented in yeast, flies, mice, and in human tissues. RE derepression has been associated with neuronal decline and many age-related degenerative diseases. However, the cause/consequence relation between RE derepression and aging remains unclear. Our current aim is to study the causality and the mechanisms of RE derepression in aging neurons by applying state-of-the-art tools in molecular genetics and genomics. In the longer-term, our objective is to screen for prophylactic drugs that impede de novo RE-mediated mutations in vivo, hopefully preventing age-related neuronal decline and thereby prolonging the productive life of post-mitotic neurons. We believe that the findings from this work could have a strong impact in human health.
Molecular mechanisms of peripheral neuropathies
Neuropathies are a group of diseases that affect normal function of the peripheral nerves connecting the central nervous system to the rest of the body. Neuropathies can be induced by treatments (e.g., certain medications or chemotherapy), be associated to diseases (e.g., diabetes and auto-immune diseases), or be hereditary. The human Rho Guanine Exchange Factor (RhoGEF) 10 gene (ARHGEF10) is one of the ~50 genes have been associated to Charcot-Marie-Tooth disease, a heterogeneous group of hereditary neuropathies in human, both as a hereditary factor associated with hypomyelination of peripheral nerves and as a gene associated with chemotherapy-induced peripheral neuropathy. Furthermore, a loss-of-function mutation in ARHGFE10 has also been associated with a clinically similar inherited polyneuropathy in Leonberger dogs. How mutation of ARHGEF10 leads to these diseases is unclear. Members of the ARHGEF10-like family are found throughout metazoans, suggesting they have had a critical role in metazoan life history. To gain insight into ARHGEF10 function and its role in peripheral neuropathy we study the biology of the sole ARHGEF10 orthologue in Drosophila, darhgef10. We are also interested in developing human induced pluripotent stem cell models where we can directly study the function of human ARHGEF10 during cellular differentiation in collaboration with the Mhlanga lab, CSIR.
New technologies for cellular targeting
A major challenge in biology and biomedicine is to genetically access a specific cellular type, be it in a healthy or diseased state, within complex and highly adaptable multicellular organisms. Most gene delivery systems are profoundly limited by the technology available to access particular cellular types in a limited set of organisms. An alternative to these procedures is to use methods that do not rely on cell specific strategies to deliver genetic materials to cells. For instance, to use a system that delivers the desired genetic material unrestrictedly to as many cells as possible in the complex organism and work out the cell specificity post-delivery. Considering that such cell-unspecific systems are becoming available (e.g., particular viruses or chemical-based delivery systems), the challenge becomes to have an unlimitedly versatile genetic means of activating any particular genetic message exclusively within a target cell type. Such methodology would have a major impact in multiple domains of life science, including the possibility of designing novel medical tools and therapies for diseases such as metastatic cancer and beyond, as well as providing new means to develop improved crops, livestock and biotechnologies. The objective of this project is to develop this technology.
- - Developmental Biology
- - Physiology and Metabolism
- - Neurodegenerative Disease and Ageing
- - Neuroendocrinology
- - Drosophila genetics
- - Cancer Biology
- - Molecular and Cell Biology
- - Molecular Evolution
- - Biotechnology/Genetic Engineering
The Discoveries Center mission is to perform world-leading research in regenerative and precision medicine, by anchoring research activities of the best research groups in Portugal, promoting excellence, advanced training, increasing performance, translational research outputs and commercialization strategies that can, in the long-run generate an important economic impact, besides impacting the quality of life of an ageing European population affected by neurodegenerative, cardiovascular and musculoskeletal diseases.
- FCT National Grant, AAC-02/SAICT/2017/031071, Portugal 2018-2021.
- FCT National Grant, AAC-02/SAICT/2017/030753, Portugal 2018-2021.
- MIT Portugal Program, MIT-EXPL/BIO/0097/2017, Co-PI: T Lu/C Brito/J Ramalho.
- FAPESP Grant 2016/09659-3, Brazil 2017-2019 (Co-PI with Prof. Tatiana Torres).
- PTDC/BEXBCM/1370/2014 FCT Grant, Portugal 2016-2018.
- iNOVA4Health UID/Multi/04462/2013 Unit Seed Project, FCT Portugal 2015-2017 (Co-PI with Drs Catarina Brito and José Ramalho).
- 2012 FCT Investigator Programme “Development Grant” 2013-2018.
- Marie Curie Career Integration Grant (FP7-PEOPLE-2013-CIG) "FLY-PHY" 2013-2017.
- Heredia F, Volonté Y, Pereirinha J, Fernandez-Acosta M, Casimiro AP, Belém CG, Viegas F, Tanaka K, Menezes J, Arana M, Cardoso GA, Macedo A, Kotowicz M, Prado Spalm FH, Dibo MJ, Monfardini RD, Torres TT, Mendes CS, Garelli A, Gontijo AM. The steroid-hormone ecdysone coordinates parallel pupariation neuromotor and morphogenetic subprograms via epidermis-to-neuron Dilp8-Lgr3 signal induction. Nat Commun. 2021 Jun 7;12(1):3328. doi: 10.1038/s41467-021-23218-5.
- Heredia F, Volonté Y, Pereirinha J, Fernandez-Acosta M, Casimiro AP, Belém CP, Viegas F, Tanaka K, Arana M, Cardoso G, Macedo M, Kotowicz M, Prado Spalm F, Dibo MV, Monfardini RD, Torres TT, Mendes CS, Garelli A*, Gontijo AM*. Innate Behavior Sequence Progression by Peptide-Mediated Interorgan Crosstalk. bioRxiv 2020.10.10.334540; doi: 10.1101/2020.10.10.334540.
- Imambocus BN, Wittich A, Tenedini F, Zhou F, Hu C, Sauter K, Varela EM, Herédia F, Casimiro AP, Macedo A, Schlegel P, Yang R, Miguel-Aliaga I, Pankratz M,Gontijo AM, Cardona A, Soba P. Discrete escape responses are generated by neuropeptide-mediated circuit logic. bioRxiv 2020.09.22.307033; doi: https://doi.org/10.1101/2020.09.22.307033
- Macedo A, Gontijo AM. The intersectional genetics landscape for humans. Gigascience. 2020 Aug 1;9(8):giaa083. doi: 10.1093/gigascience/giaa083. PMID: 32761099
- Gontijo AM, Garelli A. The biology and evolution of the Dilp8-Lgr3 pathway: A relaxin-like pathway coupling tissue growth and developmental timing control. Mech Dev. 2018 Apr 30. pii: S0925-4773(18)30072-8. doi: 10.1016/j.mod.2018.04.005. [Epub ahead of print]
- Garelli A, Heredia F, Casimiro AP, Macedo A, Nunes C, Garcez M, Dias AR, Volonte YA, Uhlmann T, Caparros E, Koyama T, Gontijo AM. Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing. Nat Commun. 2015 Oct 29. 6:8732. doi: 10.1038/ncomms9732.
- de Castro Marcondes JP, de Oliveira ML, Gontijo AM, de Camargo JL, Salvadori DM. Genetic instability persists in non-neoplastic urothelial cells from patients with a history of urothelial cell carcinoma. PLoS One. 2014 Jan 22;9(1):e86162. PMID: 24465937
- Garelli A, Gontijo AM, Miguela V, Caparros E, Dominguez M. Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science. 2012 May 4;336(6081):579-82. PMID: 22556250.
- Gontijo AM, Miguela V, Whiting MF, Woodruff RC, Dominguez M. Intron retention in the Drosophila melanogaster Rieske Iron Sulphur Protein gene generated a new protein. Nat Commun. 2011;2:323. PMID: 21610726.
- Gontijo AM, Aubert S, Roelens I, Lakowski B. Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of sel-12 mutants with amber stop mutations in Caenorhabditis elegans. BMC Genet. 2009 Mar 20;10:14. PMID: 19302704.
- Lopez-Rubio JJ, Gontijo AM, Nunes MC, Issar N, Hernandez Rivas R, Scherf A. 5′ flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites. Mol Microbiol. 2007 Dec;66(6):1296-305. PMID: 18028313.
- Pinhal D, Gontijo AM, Reyes VA, Salvadori DM. Viable human buccal mucosa cells do not yield typical nucleoids: impacts on the single-cell gel electrophoresis/Comet assay. Environ Mol Mutagen. 2006 Mar;47(2):117-26. PMID: 16258922.
- Freitas-Junior LH, Hernandez-Rivas R, Ralph SA, Montiel-Condado D, Ruvalcaba-Salazar OK, Rojas-Meza AP, Mâncio-Silva L, Leal-Silvestre RJ, Gontijo AM, Shorte S, Scherf A. Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell. 2005 Apr 8;121(1):25-36. PMID: 15820676.
- Alves A, De Miranda Cabral Gontijo AM, Salvadori DM, Rocha NS. Acute bacterial cystitis does not cause deoxyribonucleic acid damage detectable by the alkaline comet assay in urothelial cells of dogs. Vet Pathol. 2004 May;41(3):299-301. PMID: 15133185.
- Gontijo AM, Green CM, Almouzni G. Repairing DNA damage in chromatin. Biochimie. 2003 Nov;85(11):1133-47. PMID: 14726019.
- Azevedo L, Gomes JC, Stringheta PC, Gontijo AM, Padovani CR, Ribeiro LR, Salvadori DM. Black bean (Phaseolus vulgaris L.) as a protective agent against DNA damage in mice. Food Chem Toxicol. 2003 Dec;41(12):1671-6. PMID: 14563392.
- de Miranda Cabral Gontijo AM, Barreto RE, Speit G, Valenzuela Reyes VA, Volpato GL, Favero Salvadori DM. Anesthesia of fish with benzocaine does not interfere with comet assay results. Mutat Res. 2003 Jan 10;534(1-2):165-72. PMID: 12504765.
- Gontijo AM, Marcondes JP, Elias FN, de Oliveira ML, de Lima RO, Salvadori DM, de Camargo JL. DNA damage in cytologically normal urothelial cells of patients with a history of urothelial cell carcinoma. Environ Mol Mutagen. 2002;40(3):190-9. PMID: 12355553.
- Gontijo AM, Elias FN, Salvadori DM, de Oliveira ML, Correa LA, Goldberg J, Trindade JC, de Camargo JL. Single-cell gel (comet) assay detects primary DNA damage in nonneoplastic urothelial cells of smokers and ex-smokers. Cancer Epidemiol Biomarkers Prev. 2001 Sep;10(9):987-93. PMID: 11535552.
Current and Former Collaborators
- Dr. Alysson Muotri, UCSD, USA.
- Dr. Catarina Brito, iBET, Portugal
- Dr. Darren Obbard, University of Edinburgh, UK
- Dr. Esther Caparros, UMH, Spain
- Dr. Herve Acloque, INSERM, France
- Dr. Musa M. Mhlanga, CSIR, South Africa
- Dr. Rodrigo E. Barreto, UNESP, Brazil
- Dr. Silvano Piazza, LNCIB, Italy
- Takashi Koyama, IGC, Portugal
- Prof. Tatiana Torres, USP, Brazil
- Thomas Uhlmann, Dualsystems Biotech AG, Switzerland
- Dr. Toshie Kai, Temasek Life Sciences Laboratory, Singapore
- THT-TripleHelix Technologies, Portugal