e-mail: sanchez at neuro dot utah dot edu

Professor of Neurobiology and Anatomy Investigator, Howard Hughes Medical Institute The Sánchez Lab Cellular Neuroscience Developmental Neuroscience Molecular Neuroscience

B.S. 1986 Vanderbilt University; Ph.D. 1992, University of Cincinnati College of Medicine; Post-Doctoral Fellow 1994-95, and Staff Associate 1995-2001, Carnegie Institution of Washington, Dept. of Embryology

RESEARCH:

Regeneration is a fundamental attribute of all living things, whether it be simple tissue restoration or the complete replacement of lost body parts such as limbs, tails, or even heads. The first formal studies on regeneration were carried out in crustaceans by René-Antoine Ferchault de Réaumur (1683-1757), and in hydra by Abraham Trembley (1710-1784) over 250 years ago. A long-standing problem of biology, regeneration in metazoans still awaits a satisfactory mechanistic explanation.

My laboratory's goal is to identify and characterize the molecular components underpinning regeneration. To this end, we have chosen to study the freshwater planarian or flatworm Schmidtea mediterranea. The choice of these animals as a model system is based upon four of their most salient biological properties: 1) robust regenerative abilities; 2) uncanny developmental plasticity; 3) the existence of sexual and asexual biotypes; and 4) the presence of a large subpopulation of stem cells in their body plan. In addition, an extensive and detailed body of "pre-molecular" literature exists on these animals, dating back to the work of the German naturalist Peter Simon Pallas (1741-1811), and reaching its zenith at the turn of the 20th century under the inquisitive minds of Thomas Hunt Morgan (1866-1945) and C. M. Child (1869-1954). For most of the remainder of the 20th century, however, planarians failed to attract the attention of modern molecular biology.

To better understand the biology of these intriguing animals, we have endeavored to develop molecular tools for its study. We have been aided in this pursuit by the ease of culture in the laboratory of S. mediterranea. For instance, we have established clonal lines of both sexual and asexual strains, which facilitate molecular studies. Currently, work being carried out in my laboratory involves the following lines of investigation:

Expression Profiling of Planarian Regeneration: the temporal transformation of regenerating tissues is being defined at the gene expression level using microarray technology. My laboratory has sequenced over 4,000 non-redundant cDNA clones from a clonal line of S. mediterranea. These cDNAs have been printed on microarrays and changes in their expression levels are being monitored under a variety of experimental conditions. In addition, spatial expression patterns of this cDNA collection is being determined by automated, whole-mount in situ hybridizations. The information derived from these studies will provide us with a comprehensive view of the molecular choreographies being deployed by a metazoan during regeneration.

Loss-of-function assays: We have shown that gene expression in these animals can be silenced by double-stranded RNA. At the moment, we are engaged in a double-stranded-RNA-interference screen aimed to identify genes capable of disturbing regenerative events. The genes identified in this screen, combined with the microarray analyses described above, will help us delineate the epistatic interactions that are required to trigger regenerative events in S. mediterranea.

Stem cell characterization: In planarians, cell division is entirely restricted to a subpopulation of free mesenchymal stem cells known as neoblasts. Recently we have succeeded in specifically labeling planarian stem cells using BrdU and mitotic markers. In addition the EST project has identified a variety of genes expressed in the planarian stem-cells. Such markers and reagents offer a unique opportunity to delineate the mechanisms operating behind the control and rate of the cell cycle of stem cells, and their eventual determination and differentiation during both normal cell turnover and in response to wounding and regeneration.

Research in the laboratory also involves the creation of transgenic planarians using planarian stem cells as vectors for the introduction of DNA, and efforts are being made to study the embryogenesis of the freshwater planarian which was last described in detail in 1917 by Fulinski. Altogether, the available molecular tools and markers, and the analytical work obtained from their use should pave the way for a vertical integration of what is learned from planarians into the study of regeneration in higher organisms.

Selected Publications

Sánchez Alvarado, A. (2006) Planarian Regeneration: Its End is Its Beginning. Cell, 124(2):241-245.

Sánchez Alvarado, A., and Tsonis, P.A. (2006) Bridging the Regeneration Gap: Genetic Insights from Diverse Animal Models. Nature Reviews | Genetics, 7:873:884.

Reddien, P.W., Oviedo, N.J., Jennings, J.R., Jenkin, J.C., and Sánchez Alvarado, A. (2005) SMEDWI-2 Is a PIWI-Like Protein That Regulates Planarian Stem Cells. Science, 310:1327-1330.

Reddien, P.W., Bermange, A.L., Murfitt, K.J., Jennings, J.R., and Sánchez Alvarado, A. (2005) Identification of Genes Needed for Regeneration, Stem Cell Function, and Tissue Homeostasis by Systematic Perturbation in Planarians. Developmental Cell, 8:635-649.

Reddien, P.W., and Sánchez Alvarado, A. (2004) Fundamentals of Planarian Regeneration. Annual Review of Cell and Developmental Biology, 20:725-757.

Sánchez Alvarado, A. (2004) Regeneration and the need for simpler model organisms. Philosophical Transactions of the Royal Society of London. Series B, 359:759-763.

Sánchez Alvarado, A. (2003) The freshwater planarian Schmidtea mediterranea: embryogenesis, stem cells and regeneration. Current Opinion in Genetics and Development, 13:438-444.

Oviedo, N.J., Newmark, P.A., and Sánchez Alvarado, A. (2003) Allometric Scaling and Proportion Regulation in the Freshwater Planarian Schmidtea mediterranea. Developmental Dynamics, 226:326-333.

Sánchez Alvarado, A., Newmark, P.A., Robb, S.M.C., and Juste, R. (2002) The Schmidtea mediterranea database as a molecular resource for studying platyhelminthes, stem cells and regeneration. Development 129:5659-5665.

Cebrià, F., Kobayashi, C., Umesono, Y., Nakazawa, M., Mineta, K., Ikeo, K., Gojobori, T., Itohk, M., Tairak, M., Sánchez Alvarado, A., and Agata, K. (2002) FGFR-related gene nou-darake restricts brain tissues to the head region of planarians. Nature, 419:620-624.

Newmark, P.A., and Sánchez Alvarado, A. (2002) Not your father's planarian: a classic model enters the era of functional genomics. Nature Reviews Genetics, Mar;3(3):210-219.

Sánchez Alvarado, A. (2000) Regeneration in the Metazoans: Why Does it Happen? BioEssays, 22:578-590.

Newmark, P.A., and Sánchez Alvarado, A. (2000) Bromodeoxyuridine Specifically Labels the Regenerative Stem Cells of Planarians. Developmental Biology, 220:142-153.

Sánchez Alvarado, A., and Newmark, P.A. (1999) dsRNA Specifically Disrupts Gene Expression During Planarian Regeneration. Proceedings of the National Academy of Sciences, USA, 96:5049-5054.

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