Principal investigator Dr. Giraldez
Summary of research lines
General. The function of the brain depends on the activity of an enormous number of different neurones that establish stereotyped connections. The generation of such diversity arises during embryonic development and depends on a precise balance between cell proliferation and the activation of differentiating programs. The central question addressed the work is that of the molecular mechanisms that dictate the state of neural progenitors, and how cell-division is coupled to differentiation. However, the diversification of neuronal subtypes in the Nervous System results from the combination of autonomous and cell-to-cell communication factors that act on neural progenitors. Therefore, one major axis of this work is to understand the interactions between determinative factors, and to define how these various environmental, intrinsic, and temporal controls are integrated within the cell. The research plan for the coming years will continue the study of the cellular and molecular basis of regionalization and cell diversification of the otic primordium. We shall further explore the major genetic pathways that are critical for neuronal and hair cell specification with two major aims: 1) To deepen further into their molecular mechanisms, and 2) to explore their interactions and nodal points in gene regulation.
Specific objectives: 1) The function of SoxB1 in the specification of neuronal and sensory precursors. We shall screen for the cellular effects and genetic and biochemical targets of Sox2 in order to understand further its cellular functions. What mechanisms regulate the differential expression of SoxB1 genes and their interaction with proneural genes, so that neuronal and hair cell production is tightly timed? Interactions between SoxB1 genes and targets will be explored using genetic and biochemical tools. Computational analysis of protein structure will be combined to identify partners of SoxB1 proteins in the inner ear. 2) Cell intrinsic and extrinsic factors regulate cell fate decisions. We shall explore the mechanisms by which Sox2 and cell-to-cell signalling pathways interact during sensory development. SoxB1, Notch, and BMP signals cooperate for the maintenance of the progenitor state and prevention of precocious differentiation. How these signals interact and if so, what is the level of that interaction? Underlying this problem is the general question of whether there is an internal clock that sets the temporal sequence of cell fate decisions and to what extent signalling mechanisms are instructive or permissive. 3) The use of stem cells to find the genetic toolkit for developing hair cells. Using the basic knowledge of embryogenesis and a battery of marker genes we shall promote the transdifferentiation of hMSCs (human bone marrow stem cells) to auditory neurons and hair cells. This will allow the better understanding of the cassette that drives neurone and hair cell specification and, moreover, it will permit to generate efficiently the quantity of precursors required for transplantation. Next to the characterization, treated stem cells will be tested for their integration in the tissue context of the inner ear. This will include injection of cells into normal and damaged avian and murine auditory systems.
The group: The group consists of one IP, Fernando Giraldez, one post-doctoral researcher, Joana Neves, and one PhD student (FPI), Jelena Petrovic. We benefit from national and international collaborations that are fundamental as intellectual and technical inputs.
Collaborations: The group has links with some laboratories with whom we exchange ideas, materials and personnel. We have permanent links with Histao Kondoh (Osaka University) for studies on Sox2, Domingos Henrique (IBM-Lisboa) for Notch and neural development, and Marcelo Rivolta (Sheffield University) and Thomas Schimmang (IBGM-CSIC) for stem-cells.
Output: The output of our work is scientific knowledge, conventionally published in scientific journals and communicated in research meetings. But, moreover, the study of otic progenitors and the mechanisms of cell specification and the role of signals is of potential interest for regenerative therapy. In this connection, although our work is devoted to understand basic developmental processes, collaboration with other groups will be of interest for those exploring regenerative therapies for hair-cell damage and deafness.
Recent Publications:
Pujades, C., Kamaid, A., Alsina, B. & Giraldez, F. (2006) BMP4 regulates the development of hair-cells by modulating progenitor cell survival Developmental Biology 29:55-67
Neves, J., Kamaid, A., Alsina, B., & Giraldez, F. (2007) Differential expression of Sox2 and Sx3 in neuronal and sensory progenitors of the developing inner ear of the chick. Journal of Comparative Neurology 503:487-500
Abelló, G., Khatri, S., Giráldez, F. & Alsina, B. (2007) Early regionalization of the otic placode and its regulation by the Notch signaling pathway. Mechanisms of Development 124(7-8):631-645
Bell, D., Streit, A., Gorospe, I., Varela-Nieto, I., Alsina, B. & Giráldez, F. (2008) Spatial and temporal segregation of auditory and vestibular neurons in the otic placode. Developmental Biology 322:109-120
Kamaid, A. & Giráldez, F. (2008) Btg1 and Btg2 expression during early chick development. Developmental Dynamics 237:2158-2169
Alsina, B., García-Lomana, Villà, J., Giráldez, F. (2009). Developmental Biology and Mathematics: the rules of an embryo AMS-RSME: Selected Topics in Mathematics, Development and Cancer. Ed. by F Giraldez and MA Herrero
Abelló G. , Khatri S. , Radosevic M. , Scotting P.J , Giráldez, F. , Alsina B. (2010) Independent regulation of Sox3 and Lmx1b by FGF and BMP signaling determines the neurogenic and non-neurogenic domains in the chick otic placode Developmental Biology
Kamaid, A., Neves, J. and Giráldez, F. (2010) Id gene regulation and function in the prosensory domains of the chicken inner ear: a link between BMP signaling and Atoh1. J.Neuroscience 30(34):11426-34
Neves, J., Parada, C., Chamizo, M. and Giraldez, F. (2010) Jagged1/Serrate1 regulates the restriction of Sox2 expression in the inner ear: a mechanism for sensory organ specification"