M411 Lecture: Michael Collins, PhD "Analysis of chemical perturbations in the developmental gene regulatory network of the sea urchin to elucidate mechanisms of mammalian terratogenesis"

November 29, 2012 - 12:00pm - 1:00pm

Location

Lecture Hall 43-105 CHS
United States

Chemicals that will lead to human exposure are tested for the ability to cause congenital malformations in two laboratory mammalian species.  This is a relatively “black box” approach to toxicology testing as the compound is given to the animals to determine if it causes a deleterious outcome without understanding how it produced the outcome.  For years, teratologists have attempted to delineate the mechanisms by which chemicals cause congenital malformations, with only limited success.  Part of the difficulty in detecting how chemicals could be causing abnormal developmental outcomes is attributable to the fact that the normal developmental programs in organisms are complex and not well defined.   “Gene regulatory networks (GRNs) provide system level explanations of developmental and physiological functions in the terms of the genomic regulatory code.”  (Davidson, 2010).  Thus, the GRN can molecularly define normal morphological events and therefore altered morphology must result from an alteration of the GRN.  The organism with the most extensively characterized developmental GRN is the purple sea urchin Strongylocentrotus purpuratus.  Experiments to understand the sea urchin GRN target of the anticonvulsant agent valproic acid will be described.   Valproic acid is a human teratogen causing neural tube defects as well as other malformations. The experiments have shown that valproic acid can induce aboral radialization of the sea urchin embryo.  Evidence points to the histone deacetylase activity of valproic acid causing this endpoint.  Ongoing experiments are designed to test Haber’s law and the role of time in defining the dose.  Determining the impact of valproic acid exposure on the GRN has been done by examining transcriptomics in the embryo using Nanostring nCounter technology.  Based on this analysis, the TGF-beta family member nodal appears to be a target of valproic acid but it is not clear if it is a direct or indirect target.

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