Alejandro Sánchez Alvarado, Ph.D.
Investigator of the Howard Hughes Medical Institute
Professor of Neurobiology and Anatomy
(b. 1964); 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
Office Phone: 801-581-3548
My laboratory's goal is to identify and characterize the molecular components underpinning regeneration using the freshwater planarian Schmidtea mediterranea as a model. 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 organisms, we have endeavored to develop molecular tools for its study such as the development of clonal lines, loss-of-function assays using RNA interference, a collection of >10,000 non-redundant cDNAs and batteries of immunological and fluorescent labeling reagents, as well as a recently finished and annotated genome. 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. Approximately 20,000 S. mediterranea genes are represented in these microarrays. In addition, spatial expression patterns of cDNA collections are 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 planarians can be silenced by double-stranded RNA. We have recently completed the first ever RNAi-based screen performed in planarians, which resulted in the identification of 240 specific defects on various aspects of planarian biology. Of these, 145 affect regenerative processes. This work has been published in Developmental Cell (May 2005), and the detailed characterization of two of these genes published in the journals Science (2005) and Development (2007). In addition we have begun a systematic analysis of the role of known embryonic signaling patways during the process of regeneration. Our analysis of ß-catenin loss of function was recently published in Science (2008). The genes identified in these screens, combined with the microarray analyses described above, have begun to shed mechanistic light on the epistatic interactions that are required for regeneration to occur in S. mediterranea.
Stem cell characterization: In planarians, cell division is entirely restricted to a subpopulation of adult, 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 and microarray projects have identified a variety of genes expressed in the planarian stem-cells. Such markers and reagents offer a unique opportunity to dissect in vivo stem cell biology during both normal cell turnover and in response to wounding and regeneration.
Altogether, the available molecular tools and markers, and the analytical data 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.
- Bret J. Pearson and Alejandro Sánchez Alvarado (2010) A Planarian p53 Homolog Regulates Proliferation and Self-Renewal in Adult Stem Cell Lineages. Development,137: 213-221
- Jason Pellettieri, Patrick Fitzgerald, Shigeki Watanabe, Joel Mancuso, Douglas R. Green, Alejandro Sánchez Alvarado (2010) Cell Death and Tissue Remodeling in Planarian Regeneration. Developmental Biology, 338:76-85
- Jochen C. Rink, Kyle A. Gurley, Sarah A. Elliott, and Alejandro Sánchez Alvarado (2009) Planarian Hh signaling regulates regeneration polarity and links Hh pathway evolution to cilia. Science, 326:1406-1410
- Kenneth D. Birnbaum and Alejandro Sánchez Alvarado (2008) Slicing Across Kingdoms: Regeneration in Plants and Animals. Cell, 132:697-710
- Kyle A. Gurley, Jochen C. Rink and Alejandro Sánchez Alvarado (2007) ß-Catenin Defines Head Versus Tail Identity During Planarian Regeneration and Homeostasis. Science, 319:323-327 (Editor's Choice)
- Jason Pellettieri and Alejandro Sánchez Alvarado (2007) Cell Turnover and Adult Tissue Homeostasis: From Humans to Planarians Annual Review of Genetics. 41:83-105.
- Brandi Cantarel, Ian Korf, Sofia M. C. Robb, Genis Parra, Eric Ross, Barry Moore, Carson Holt, Alejandro Sánchez Alvarado, and Mark Yandell (2007) MAKER: An Easy-to-use Annotation Pipeline Designed for Emerging Model Organism Genomes. Genome Research, doi:10.1101/gr.6743907
- Peter W. Reddien, Adam L. Bermange, Adrienne M. Kicza and Alejandro Sánchez Alvarado (2007) BMP signaling regulates the dorsal planarian midline and is needed for asymmetric regeneration. Development. 134:4043-4051
- Sofia M.C. Robb, Eric Ross and Alejandro Sánchez Alvarado (2007) SmedGD: the Schmidtea mediterranea Genome Database. Nucleic Acids Research, doi:10.1093/nar/gkm684, in press.
- Alejandro Sánchez Alvarado and Panagiotis A. Tsonis (2006) Bridging the Regeneration Gap: Genetic Insights from Diverse Animal Models. Nature Reviews Genetics. 7:873:884.
- Alejandro Sánchez Alvarado (2006) Planarian Regeneration: Its End is Its Beginning. Cell, 124(2):241-5.
- Peter W. Reddien, Néstor J. Oviedo, Joya R. Jennings, James C. Jenkin, and Alejandro Sánchez Alvarado (2005) SMEDWI-2 Is a PIWI-Like Protein That Regulates Planarian Stem Cells. Science, 310:1327-1330.
- Peter W. Reddien, Adam L. Bermange, Kenneth J. Murfitt, Joya R. Jennings and Alejandro Sánchez Alvarado (2005) Identification of Genes Needed for Regeneration, Stem Cell Function, and Tissue Homeostasis by Systematic Perturbation in Planarians. Developmental Cell, 8:635-649.
- Alejandro Sánchez Alvarado, Phillip A. Newmark, Sofia M. C. Robb and Réjeanne Juste (2002) The Schmidtea mediterranea database as a molecular resource for studying platyhelminthes, stem cells and regeneration. Development, 129:5659-5665.
- Francesc Cebrià, Chiyoko Kobayashi, Yoshihiko Umesono, Masumi Nakazawa, Katsuhiko Mineta, Kazuho Ikeo, Takashi Gojobori, Mari Itohk, Masanori Tairak, Alejandro Sánchez Alvarado, Kiyokazu Agata (2002) FGFR-related gene nou-darake restricts brain tissues to the head region of planarians Nature, 419:620-624.
- Phillip A. Newmark and Alejandro Sánchez Alvarado (2000) Bromodeoxyuridine Specifically Labels the Regenerative Stem Cells of Planarians Developmental Biology, 220:142-153.
- Alejandro Sánchez Alvarado and Phillip A. Newmark (1999) dsRNA Specifically Disrupts Gene Expression During Planarian Regeneration. Proceedings of the National Academy of Sciences USA. 96: 5049-5054.