Dr. Marian Ros, Research Professor (CSIC)
Dra. Marian Fernández Terán, Associate Professor
María Felix Bastida, Senior Researcher
Lucía Carrera, predoctoral
Rocío Pérez Gómez, predoctoral
Marc Fernández Guerrero, predoctoral
Laura Galán, technician
We use the developing limb as a paradigmatic system in which to unravel the complex molecular networks that control pattern formation and morphogenesis. Limb development initiates with the accumulation under the surface ectoderm of a cluster of proliferating limb progenitor cells. During subsequent development, these undifferentiated progenitors grow, organize and differentiate to form a perfectly shaped and fully functional limb.
Along our trajectory, we have contributed to the identification of the molecular basis of the signaling centers operating in the limb bud. Areas of continuous interest in the lab include the specification of proximo-distal fates to form the typical three-segmented tetrapod limb, the formation and function of the apical ectodermal ridge, one major signaling center in the bud and the control of digit number and identity.
Recently, searching to unravel the molecular basis of pentadactyly, we have characterized several murine models with oligo/polydactyly, common human limb malformations. We found that the removal of
5’Hox genes produced severe polydactyly of thin, short, and densely packed digital rays. These phenotypes are concordant with a Turing-type mechanism controlling digit patterning and Hox genes modulating of the wavelength (Sheth et al., 2012).
We have also recently identified the crucial role played by Sp6 and Sp8, two transcription factors members of the Sp family, in the limb ectoderm. In the absence of these two factors, no limbs form. Furthermore, the progressive reduction in the dose of
Sp6;Sp8gene products leads to a spectrum of limb malformations the severity of which correlates with the available Sp dosage. The molecular characterization of the mutant limbs supports the involvement of Sps in proximodistal and dorsoventral patterning by controllin
Subjects of present research in the lab include:
- the regulation of patterning and differentiation in the proximo-distal axis of the limb bud and the reevaluation of the current models
- the functional role of Sp6 and Sp8 transcription factors in limb development
- the crosstalk and interactions between signaling pathways during limb development
- the role of Hox and Gli3 genes in the control of the number of digits in the tetrapod limb
- the cellular and molecular basis of the Caudal dysgenesis and Sirenomelia malformation
Ministerio de Economía y Competitividad: "ANÁLISIS DE LA DINÁMICA DE LA EXPRESIÓN GÉNICA DURANTE LAS INTERACCIONES EPITELIO-MESENQUIMATOSA EN LA EXTREMIDAD". Reference: BFU2014-57216-P. Investigador responsable: M. A. Ros
Relevant publications (last 10 years)
Intrinsic properties of limb bud cells can be differentially reset. Saiz-Lopez P, Chinnaiya K, Towers M, Ros MA.
Development. 2017 Feb 1;144(3):479-486. [PubMed]
Ectoderm-mesoderm crosstalk in the embryonic limb: The role of fibroblast growth factor signaling. Mariani FV, Fernandez-Teran M, Ros MA
Dev Dyn. 2017 Apr;246(4):208-216. [PubMed]
CathepsinKCre mediated deletion of βcatenin results in dramatic loss of bone mass by targeting both osteoclasts and osteoblastic cells. Ruiz P, Martin-Millan M, Gonzalez-Martin MC, Almeida M, González-Macias J, Ros MA.
Sci Rep. 2016 Nov 2;6:36201. [PubMed]
HOX13 proteins: the molecular switcher in Hoxd bimodal regulation. Ros MA.
Genes Dev. 2016 May 15;30(10):1135-7. doi: 10.1101/gad.283598.116. [PubMed]
An intrinsic timer specifies distal structures of the vertebrate limb. Saiz-Lopez P, Chinnaiya K, Campa VM, Delgado I,
Ros MA, Towers M.
Nat Commun. 2015 Sep 18;6:8108. [PubMed]
Sp6 and Sp8 Transcription Factors Control AER Formation and Dorsal-Ventral Patterning in Limb Development. Haro E, Delgado I, Junco M, Yamada Y, Mansouri A, Oberg KC,
PLoS Genet. 2014 Aug 28;10(8):e1004468. doi: 10.1371/journal.pgen.1004468. [PubMed]
Long bone development requires a threshold of Hox function. González-Martín MC, Mallo M,
Dev Biol. 2014 Aug 15;392(2):454-65. doi: 10.1016/j.ydbio.2014.06.004.
Forward to the special issue on Hox/Tale transcription factors in development and disease. Wellik DM, Torres M,
Dev Dyn. 2014 Jan;243(1):1-3. doi: 10.1002/dvdy.24098. Epub 2013 Dec 9.
Evidence that the limb bud ectoderm is required for survival of the underlying mesoderm. Fernandez-Teran M,
Ros MA, Mariani FV.
Dev Biol. 2013 Sep 15;381(2):341-52. doi: 10.1016/j.ydbio.2013.06.032. [PubMed]
Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth. Sheth R, Grégoire D, Dumouchel A, Scotti M, Pham JM, Nemec S, Bastida MF,
Ros MA, Kmita M.
Development. 2013 May;140(10):2130-8. doi: 10.1242/dev.089409. [PubMed]
Sheth R, Bastida MF, Kmita M, Ros M. (2014). "Self-regulation", a new facet of Hox genes' function. Dev Dyn. 2014 Jan;243(1):182-91.
Fernandez-Teran M, Ros MA, Mariani FV (2013). Evidence that the limb bud ectoderm is required for survival of the underlying mesoderm. Dev Biol. 2013 Sep 15;381(2):341-52
Sheth R, Grégoire D, Dumouchel A, Scotti M, Pham JM, Nemec S, Bastida MF, Ros MA, Kmita M. (2013). Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth. Development. 2013 May;140(10):2130-8.
Sheth R, Marcon L, Bastida MF, Junco M, Quintana L, Dahn R, Kmita M, Sharpe J, Ros MA. (2012) Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism. Science. 2012 Dec 14;338(6113):1476-80.
Garrido-Allepuz C, González-Lamuño D, Ros MA. (2012) Sirenomelia phenotype in bmp7;shh compound mutants: a novel experimental model for studies of caudal body malformations. PLoS One. 2012;7(9):e44962.
- Roselló-Díez A., Ros M.A. and Torres M.
(2011). Diffusible signals, not autonomous mechanisms determine the main proximodistal limb subdivision. Science.2011; 332:1086-1088.
- Cooper K.L., Hu J K-H, Berge D., Fernandez-Teran M, Ros M.A. and Tabin C.J. (2011). Proximal-distal patterning of the vertebrate limb is initiated by altered exposure to secreted signals. Science (in press)
- Garrido-Allepuz, C., Haro, E., Gonzalez-Lamuño, D., Martinez-Frías, M.L., Bertocchini, F. and Ros M.A. (2011) Sirenomelia: A Clinical and Experimental Review. Disease Models and Mechanism (in press)
- Talamillo, A., Delgado, I., Nakamura, T., De-Vega S., Yoshitomi Y, Unda F, Birchmeier W, Hamada, Y., Ros, M.A. (2010). Role of epiprofin, azinc-finger transcription factor, in limb development. Developmental Biology 337
- Galoway, J.L., Delgado, I., Ros, M.A. and Tabin, C.J. (2009). A Reevaluation of X-Irradiation Induced Phocomelia and Proximodistal Limb Patterning. Nature 60:400-404.
- Dominguez-Frutos, E., Vendrel, V., Alvarez, Y., Zelarayan, L.C., Lopez-Herandez, I., Ros, M., Schimmang, T. (2009). Tissue-specific requirements for FGF8 during early inner ear development. Mechanisms of Development 126:873-881.
- Alvarez-Medina R., Le Dreau G., Ros M., Marti, E. (2009) Hedgehog activation is required upstream of Wnt signalling to control neural progenitor proliferation. Development 136: 3301- 3309.
- Bastida, M.F., Sheth, R. and Ros, M.A. (2009) A Bmp/Shh negative feedback loop serves to restrict Shh expresion during limb development. Development 136: 3779- 3789.
- Delgado, I., Dominguez-Frutos, E., Schimmang, T. and Ros, M.A. (2008) The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of anterior autopod through BMP-mediated cell death. Developmental Dynamics 237: 649-658.
- Fernández-Terán, M.A. and Ros, M.A. (2008). The apical ectodermal ridge: Signaling pathways involved. International Journal Developmental Biology 52:857-871.
- Bastida, M.F. and Ros, M.A. (2008). How do we get a perfect complement of digits? Current Opinion in Genetics and Development 18:374-380.
- López-Gracia, M.L. and Ros, M.A. (2007). Left-right asymmetry in vertebrate development. Advances in Anatomy, Embryology and Cell Biology. ISBN: 3-540-36347-5
- Sheth, R., Bastida, M.F. and Ros, M.A. (2007). Hoxd and Gli3 genes interact to control digit number. Developmental Biology 310:430-441.
- Fernández-Terán, M.A., Hinchliffe, J.R. and Ros, M.A. (2006). Birth and death of cells in limb development. A mapping study. Developmental Dynamics 235:2521-2537.
- Talamillo, A., Bastida, Fernández-Terán, M.A. and Ros, M.A. (2005). Limb development and the control of the number of digits.Clinical Genetics 67:143-153.
- Bastida, M.F., Delgado, M.D., Wang, B., Fallon, J.F., Fernández-Terán, M.A. and Ros, M.A. (2004) The levels of Gli3 repressor correlate with Bmp4 expression and apoptosis during limb development.Development Dynamics 231: 148-160.
- Ros, M.A., Dhan, R., Fernández-Terán, M.A., Rashka, K., Caruccio, N.C., Bitgood, J.J., Lancman, J.J. and Fallon, J.F. (2003). The chick oligozeugodactyly (ozd) mutant lacks sonic hedgehog function in the limb. Development 130:527-537
- Fernández-Terán, M.A., Piedra, M.A., Rodriguez-Rey, J.C., Talamillo, A., and Ros, M.A. (2003). Pattern of expression and regulation of eHand during limb bud development. Developmental Dynamics 418:539-544