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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

Research

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.

Our laboratory is also involved in the sequencing and assembly of the S. mediterranea genome, as well as the creation of transgenic planarians. In addition, 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.

References