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Alejandro Sanchez Alvarado

Professor of Neurobiology and Anatomy

B.S. Vanderbilt University

Ph.D. University of Cincinnati College of Medicine

Research

References

sanchez@neuro.utah.edu

Alejandro Sanchez Alvarado's Lab Page

Alejandro Sanchez Alvarado's PubMed Literature Search

Alejandro Sanchez Alvarado's Howard Hughes Medical Institute Page

Research

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.

References