Genetics and Development laboratory

Giorgio Roberto Merlo - PI

Full Professor of Developmental biology anche cellular neurobiology - Department of Molecular Biotechnology and Health Sciences, University of Torino

Main group members

Carla Liaci Dottoranda
Astrid Saraceni Assegnista ricerca
Beatrice Savarese Assegnista ricerca
Giovanni Catapano Studente Magistrale
Elena Ferretti Studentessa Magistrale
Emma Leonetti Studentessa Magistrale
Lorenzo Licari Studente Magistrale

Research Activity

Development of the Olfactory and GnRH System

The development of the olfactory neurons is associated to the genesis and migration of the GnRH neuroendocrine neurons, a complex process that is specifically impaired in the Kallmann Syndrome. The molecules involved in guidance and connectivity of olfactory axons are not well known. We are investigating the role of specific disease genes and microRNAs for olfactory/GnRH development, combining transcription-profiling, analysis of conserved co-expression and specific animal models. Zebrafish strains with fluorescent neurons, such as GnRH3::GFP, turn out useful to image the effect of exposure to endocrine-interfering compounds or other contaminants on the development of hypothalamic neurons.

Development and Maturation of Inhibitory Neurons

Using Neural Stem cells in vitro and specific mutant mouse strains, the team aims to clarify a molecular signature for GABA+ differentiation, and to comprehend the role of Dlx genes in this process. Current results indicate that alterations of the migration, differentiation and neuritogenesis of inhibitory neurons affect cognitive and memory functions of the hippocampus and may contribute to the risk of epilepsy.

The RacGTPase and Models of Intellectual Disability

The small GTPases RhoA, Rac1 and cdc42 have been implicated in genetically transmitted Intellectual Disability (ID) conditions, either directly or upon mutation of one of their several regulators in developing neurons. In the case of Rac1 it appears that most genetic mutations causing ID result in a hypoactive Rac1. Based on our previous work on the protein ArhGAP15, a negative regulator of Rac1, we can hypothesize that interfering with the protein::protein interaction between ArhGAP15 and Rac1 should result in hyperactivation of Rac1. This applied to the condition of hypoactive Rac1 causing ID might restore normal activity and the development of normal neuronal circuitry. We are currently setting up cellular models to prove this hypothesis.

FUTURE RESEARCH PLANS

Recently the team is implementing a program for the use of human pluripotent stem cells to explore the effects of pathogenic mutations on human brain development. In particular, the experimental work focuses on two selected disease-genes, TRIO and ArhGEF6, that encode for proteins that regulate the dynamic of actin cytoskeleton, whose mutations cause hereditary Microcephaly and ID. Human iPSc have been mutagenized and are currently being analysed for neurogenesis, kinetic and orientation of cell division, neuronal differentiation, morphogenesis and neuritogenesis, 3D organisation, network formation. A new project, in collaboration with Dept. of Life Science, deals with the impact of microplastics (MPs) and Endocrine Disrupting Chemicals (EDC) on living organisms. It has been recently found that they can distribute systematically within an organism and they are associated with disease risk. At present there is no evidence of a direct action of MPs, there is growing evidence of the potential of MPs to be vehicles of environmental contaminants, including EDC. We aim to evaluate the impact of MP and EDC on health, in particular on reproduction and metabolism. Studies are in progress on zebrafish embryos and on mammalian cells (adipocytes, hepatocytes, neurons) exposed to environmentally relevant doses.

FUNDING ID (PAST 5 YEARS)

Eit Food EU program, 2019. Consumers and Environmental Safety: Food Packaging and Kitchenware Coordinator, E. 65.000
Telethon Foundation, Research Grant 2021 GGP20039. Rac GTPase in Intellectual Disability: preclinical opportunities from interfering with a Rac1 protein::protein interaction. Principal Investigator E. 185,000
MUR PRIN 2022. Neural cytoskeleton and Rho GTPases in human models of Intellectual Disability and Microcephaly. Principal Investigator, 199.000.

SELECTED PUBLICATIONS

Garafo G., Conte D., Provero P., Tomaiuolo D., Luo Z., Pinciroli P, Peano C., D’Atri I., Gitton Y., Etzion E., Gothilf Y., Gays D., Santoro M.M., Merlo G.R. (2015) The Dlx5 and Foxg1 transcription factors, linked via miRNA-9 and -200, are required for the development of the olfactory and GnRH system. Mol. Cell. Neurosci. 68: 103- 119. doi: 10.1016/j.mcn.2015.04.007 PubMed PMID: 25937343; PubMed Central PMCID: PMC4604252

Conte D, Garafo G, Lo Iacono N, Mantero S, Piccolo S, Cordenonsi D, Perez-Morga D, Orecchia V, Poli V and Merlo GR (2015) The Apical Ectodermal Ridge of Dlx5;Dlx6-/- ectrodactyly limbs shows altered Wnt5a expression and planar-cell polarity pathway, rescued by exogenous Wnt5a ligand. Hum Mol Genet. 25(4): 740-754. doi: 10.1093/hmg/ddv514. PubMed PMID: 26685160; PubMed Central PMCID: PMC4743692

Zamboni V, Armentano M, Berto G, Ciraolo E, Ghigo A, Garzotto D, Umbach A, DiCunto F, Parmigiani E, Boido M, Vercelli A, El-Assawi N, Mauro A, Priano L, Ponzoni L, Murru L, Passafaro M, Hirsch E, Merlo GR. (2018) Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis by altering actin dynamics. Scientific Report, 8: 7254. doi: 10.1038/s41598-018-25354-3. PMID 29740022

Grassi E, Santoro R, Umbach A, Grosso A, Oliviero S, Neri F, Conti L, Ala U, Provero P, DiCunto F, Merlo GR (2019) Choice of alternative polyadenylation sites, mediated by the RNA-binding protein Elavl3, plays a role in differentiation of inhibitory neuronal progenitors. Front. Cell. Neurosci. 12:518. doi: 10.3389/fncel.2018.00518

Zuccarini G, D’Atri I, Cottone E, Mackie K., Shainer I, Gothilf Y, Provero P, Bovolin P and Merlo GR (2019) Interference with the cannabinoid receptor CB1R results in miswiring of GnRH+ and AgRP1+ axons in zebrafish embryos. Int. J. Molecular Sci, special issue 21(1) pii:E168. doi:10.3390/ijms21010168. PMID: 31881740

Messina A., Pulli K., Santini S., Acierno J., Känsäkoski J., Cassatella D., Xu C., Casoni F., Malone S.A., Ternier G., Conte D., Sidis Y., Tommiska J., Vaaralahti K., Dwyer A., Gothilf Y., Merlo G.R., Santoni F., Niederländer N.J., Giacobini P., Raivio T., Pitteloud N. (2020) Neuron-derived neurotrophic factor (NDNF) is mutated in patients with Congenital Hypogonadotropic Hypogonadism, Am. J. Hum Genet, 106(1): 58-70. doi: 10.1016/j.ajhg.2019.12.003. PMID: 31883645

Liaci C., Camera M., Rando S., Caslini G., Contino S., Romano V. and Merlo GR (2021) Neuronal cytoskeleton in intellectual disability: from systems biology and modeling to therapeutic opportunities. Int. J. Molecular Sci. 22(11) 6167. doi: 10.3390/ijms22116167 PMID: 34200511

Camera M, Russo I, Zamboni V, Ammoni A, Rando S, Morellato A, Cimino I, Angelini C, Giacobini P, Oleari R, Amoruso F, Cariboni A, Franceschini I, Turco E, Defilippi P and Merlo GR (2022) p140Cap controls female fertility in mice acting via glutamatergic afferents on hypothalamic GnRH neurons. Front. Neuroscience 16: 744693. doi: 10.3389/fnins.2022.744693. eCollection 2022 PMID: 35237119

Liaci C., Prandi L., Brusco A., Pavinato L., Maldotti M., Molineris I., Oliviero S. and Merlo G.R. (2022) The emerging role of non-coding lncRNAs in Intellectual Disability and related neurodevelopmental disorders. Int. J. Mol. Sci., 23: 6118. doi: 10.3390/ijms23116118 PMID: 35682796

Liaci C., Camera M., Zamboni V., Sarò G., Ammoni A., Parmigiani E., Ponzoni L., Hidisoglu E., Chiantia G., Marcantoni M., Giustetto M., Tomagra G., Carabelli V., Torelli F., Yanagawa Y., Obata K., Hirsch E., Merlo G.R. (2022) Loss of ARHGAP15 afects the directional control of migrating interneurons in the embryonic cortex and increases susceptibility to epilepsy. Front Cell Develop Biol 10:875468. Pag 1-20 doi: 10.3389/ fcell.2022.875468

Ultimo aggiornamento: 22/01/2025