Animal models by genetic manipulation



Lluís Montoliu

Group Leader



Research summary

In our laboratory, we are interested in understanding how mammalian expression domains work and how they are organised within genomes. In particular, we focus on the identification and characterisation of genomic boundaries or insulators. By studying insulator elements, we aim to contribute to understanding of the functional and structural organization of vertebrate genomes. Insulators can be used effectively in biotechnological applications, as spacers, as boundaries, in any gene expression construct to be used in gene transfer experiments. We are searching for new insulator sequences in vertebrate genomes, through initial bioinformatic analyses.



Mojica FJ, Montoliu L.On the Origin of CRISPR-Cas Technology: From Prokaryotes to MammalsTrends Microbiol. 2016 Oct;24(10):811-20

Josa S, Seruggia D, Fernández A, Montoliu L. Concepts and tools for gene editing. Reprod Fertil Dev. 2016 Jan;29(1):1-7

Oliveros JC, Franch M, Tabas-Madrid D, San-León D, Montoliu L, Cubas P, Pazos F. Breaking-Cas-interactive design of guide RNAs for CRISPR-Cas experiments for ENSEMBL genomes. Nucleic Acids Res. 2016 Jul 8;44(W1):W267-71

Wang J, Vicente-García C, Seruggia D, Moltó E, Fernandez-Miñán A, Neto A, Lee E, Gómez-Skarmeta JL, Montoliu L, Lunyak VV, Jordan IK. MIR retrotransposon sequences provide insulators to the human genome. Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4428-37

Seruggia D, Fernández A, Cantero M, Pelczar P, Montoliu L. Functional validation of mouse tyrosinase non-coding regulatory DNA elements by CRISPR-Cas9-mediated mutagenesis. Nucleic Acids Res. 2015 May 26;43(10):4855-67


figura1MontoliuRedWe are interested in understanding the function of regulatory elements necessary to identify gene expression domains in mammalian genomes and that help to specify gene expression patterns in space and time. Our basic aim is to improve adequate interpretation of the genome, especially the function of intergenic sequences, where most regulatory elements are located, and to improve the design of gene transfer strategies applied in animal transgenesis and gene therapy.

One of the experimental models in the lab is the tyrosinase gene, which encodes an enzyme that activates synthesis of the pigment melanin, which is regulated throughout development and is tissue-specific (expressed only in melanocytes and retinal pigment epithelium cells). This locus served to identify genome boundaries or insulators, which protect the tyrosinase gene from surrounding genes. In transgenic zebrafish and mice, we use different types of gene constructs based on plasmids and artificial chromosomes, which we modify by homologous recombination to study the relevance of specific sequences. Functional analysis of regulatory elements within the intergenic sequences can be now addressed more efficiently, thanks to the new CRISPR-Cas9 gene modification system that we have implemented successfully in our laboratory.

In addition, we generated and analysed new animal models to study visual abnormalities, including anomalies that affect retina development associated with albinism, as well as other retinopathies such as achromatopsia. In transgenic mice, we identified deficiency in L DOPA (one of the intermediate metabolites in the melanin synthesis pathway) as the principal cause of the visual alterations in albinism. Within our participation in the CIBERER-ISCIII, we developed various additional animal models (transgenic and knockout) for the study of rare human diseases, performed. In collaboration with Ángel Carracedo (Universidad de Santiago de Compostela) and Carmen Ayuso (Fundación Jiménez Díaz), we have established an experimental approach for the universal genetic diagnosis of all known mutations in the various albinism genes; in cooperation with ALBA, the Spanish association in support of people with albinism, we are already applying this approach to people with albinism and their relatives.






Lluís Montoliu Principal investigator
Almudena Fernández López Postdoctoral scientist
Diego Muñoz Postdoctoral scientist
Marcos Rubio Postdoctoral scientist
Santiago Josa de Ramos Predoctoral scientist
Andrea Montero Predoctoral scientist
Julia Fernández Punzano Predoctoral scientist
Marta Cantero Technician

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