Page’s Lab

Lab Members

Jesús Page Utrilla, PI
Julio Sánchez Rufas
Mayte Parra Catalán
Alberto Viera Vicario
Ana Gil Fernández
Marta Martín Ruiz
Eva García López

Track record of the group

From the different topics we have investigated, we can highlight:

1.- Organization and assembly of axial structures on the meiotic chromosomes, such as chromatid cores, synaptomenal complex and cohesin axes. Our work on chromatid cores was pioneer on the understanding of chromosome organization during meiosis and offered a framework for the rise of the sister chromatid cohesion model to explain the segregation of chromosomes during meiosis. Over years, we were able to characterize for the first time some of the components of meiotic cohesin complexes, proposed a model for the relationship of the different axial structures of chromosomes and reported the existence of many different cohesin complexes assembled along them.

2.- Organization of specific chromosome regions such as centromeres and telomeres. Regarding centromeres, we characterized the structure and ultrastructure of different kinds of kinetochores in monocentric chromosomes, i.e. ball and cup and trilaminar ones. We proposed a model for the sequential assembly of different centromere components on mammalian meiosis and how this organization is related to the regulation of segregation during first and second meiotic division. We also studied the composition and behavior of centromeres in insect species, mainly orthopterans and hemipterans. We discovered some of the factors involved in the meiotic behavior of holocentric chromosomes and how they are able to perform an inverted meiotic sequence of segregation. Likewise, we have characterized the organization of telomeric regions, showing the changes in organization that take place during meiosis.

3.- Relation between synapsis and recombination. Using insect models of incomplete synapsis, we elucidated some of the factors that regulate the assembly of DNA repair machinery during meiosis, the localization of chiasmata and how the interference of these processes can lead to aneuploidy.

4.- Behavior of sex chromosomes during meiosis. Owing to their partial or complete asynaptic nature, sex chromosomes present a number of modifications in their structure and behavior. We have uncovered some of the mechanisms that operate on the sex chromosomes in a variety of insect and mammalian species. We proposed that the components of the synaptonemal complex play a role in the segregation of asynaptic sex chromosomes and found that these mechanisms are strikingly conserved in very distant mammals, such as marsupials, gerbils and voles.

5.- Epigenetics of meiosis. We have worked on the relationships between some of the processes occurring during meiosis, such as DNA repair and synapsis, and the regulation of transcription. We uncovered some of the epigenetic modifications related to transcription activation or inhibition at different stages of meiosis, and how they are related to the behavior of chromosomes with partial synapsis, like Robertsonian and sex chromosomes, and how epigenetic changes can have an influence on the progression of meiosis when synapsis is interfered.

Regarding the methodological approaches of our group, we have to mention two specific points:

– We have always worked in a variety of species, looking for specific features that appear in natural populations. This approach has allowed us to draw conclusions from our analyses in an evolutionary context, which is simply not possible from the study of model species.

– We have made use of advanced microscopy techniques. We introduced specific methods for the analysis of three-dimensional organization and distribution of chromosomes during meiosis. Likewise, we made use of epifluorescence, confocal, and currently super-resolution microscopy. In this sense, our images have remained as a worldwide reference for morphological studies on meiosis.

 

Most relevant publications

– Transcription reactivation during the first meiotic prophase in bugs is not dependent on synapsis. Viera A, Parra MT, Rufas JS, Page J. Chromosoma. 2017 Feb;126(1):179-194. doi: 10.1007/s00412-016-0577-6.

– Do Exogenous DNA Double-Strand Breaks Change Incomplete Synapsis and Chiasma Localization in the Grasshopper Stethophyma grossum? Calvente A, Santos JL, Rufas JS. PLoS One. 2016 Dec 22;11(12):e0168499. doi: 10.1371/journal.pone.0168499. eCollection 2016

– Alterations in chromosomal synapses and DNA repair in apoptotic spermatocytes of Mus m. domesticus. Ayarza E, González M, López F, Fernández-Donoso R, Page J, Berrios S. Eur J Histochem. 2016 Jun 14;60(2):2677. doi: 10.4081/ejh.2016.2677.

– The Robertsonian phenomenon in the house mouse: mutation, meiosis and speciation. Garagna S, Page J, Fernandez-Donoso R, Zuccotti M, Searle JB. Chromosoma. 2014 Dec;123(6):529-44. doi: 10.1007/s00412-014-0477-6.

– Aneuploidy in spermatids of Robertsonian (Rb) chromosome heterozygous mice. Manieu C, González M, López-Fenner J, Page J, Ayarza E, Fernández-Donoso R, Berríos S. Chromosome Res. 2014 Dec;22(4):545-57. doi: 10.1007/s10577-014-9443-7.

– Bivalent associations in Mus domesticus 2n = 40 spermatocytes. Are they random? López-Fenner J, Berríos S, Manieu C, Page J, Fernández-Donoso R. Bull Math Biol. 2014 Aug;76(8):1941-52. doi: 10.1007/s11538-014-9992-0.

– Chromatin organization and remodeling of interstitial telomeric sites during meiosis in the Mongolian gerbil (Meriones unguiculatus). de la Fuente R, Manterola M, Viera A, Parra MT, Alsheimer M, Rufas JS, Page J. Genetics. 2014 Aug;197(4):1137-51. doi:10.1534/genetics.114.166421.

– Robertsonian chromosomes and the nuclear architecture of mouse meiotic prophase spermatocytes. Berríos S, Manieu C, López-Fenner J, Ayarza E, Page J, González M, Manterola M, Fernández-Donoso R. Biol Res. 2014 May 14;47:16. doi: 10.1186/0717-6287-47-16.

– B1 was the ancestor B chromosome variant in the western Mediterranean area in the grasshopper Eyprepocnemis plorans. Cabrero J, López-León MD, Ruíz-Estévez M, Gómez R, Petitpierre E, Rufas JS, Massa B, Kamel Ben Halima M, Camacho JP. Cytogenet Genome Res. 2014;142(1):54-8. doi: 10.1159/000356052.

 

 

 

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Schematic representation of assembly of different axial structures on meiotic chromosomes. Image taken from Valdeolmillos et al., 2007 PLoS Genetics

 

 

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Schematic representation of sex chromosome behavior in marsupials, showing the role of synaptonemal complex proteins in their pairing and segregation. Image taken from Page et al., 2006 PLoS Genetics

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Schematic representation of the epigenetic modifictions of sex chromosoems during first meiotic prophase. Image taken from Page et al., 2012 Chromosoma

Aim of the research work

Our current research project is focused on the study of how meiosis and sex chromosome evolution are related to each other. Mammal sex chromosomes are highly differentiated: the X chromosome is large and gene-rich while the Y is a tiny and mostly heterochromatic chromosome. The mammalian X and Y chromosomes evolved from an autosomal pair about 166 million years ago. During this period, the male-specific Y has progressively lost active genes. This differentiation leaded to the appearance of somatic and meiotic mechanisms of sex chromosome inactivation (dosage compensation) and also posed severe problems for the correct distribution of chromosomes at meiosis. Our hypothesis is that the steps of sex chromosome differentiation required the evolution of specialised meiotic mechanisms. To test this, we are currently comparing meiotic synapsis, recombination and segregation of sex chromosomes, along with their epigenetic modifications, in mammals that represent different steps of the process of XY differentiation:

– Initial differentiation, like XX/XX chromosome system in some Asian vole species of genus Ellobius.

– Intermediate stages, like the neo-X and neo-Y chromosomes of some marsupials and mouse species.

– Complete differentiation, in which sex chromosomes have completely lost their homology, present in some marsupials and rodents

– Finally, the complex chromosome system of monotremes, which represent an extraordinary chain of ten sex chromosomes.

All these species are available to us through collaborations with laboratories in Europe, America and Australia. We are finding new patters of sex chromosome pairing and segregation that will offer new ways to understand the constrains that meiosis may impose into sex chromosome evolution. Moreover, we are trying to make a contribution into the evolution and regulation of meiotic sex chromosome inactivation and how the expression of sex chromosome-linked genes can influence the progression of meiosis.

Research identification links

https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/53571535/?sort=date&direction=ascending

ORCID:(0000-0001-8381-324X)

Research ID (K-6121-2014)

web of the group