Gunter Wagner

Gunter Wagner's picture
Alison Richard Professor of Ecology and Evolutionary Biology Ecology and Evolutionary Biology; Department of Obstetrics, Gynecology and Reproductive Sciences - Yale University; and Adjunct Professor of Obstetrics and Gynecology - Wayne State University
Address: 
300 Heffernan Dr #B31, West Haven, CT 06516
203-737-3091; 203-432-9998
Office Location: 
OML 327A
Research Areas: 
Homology/character identity/novelty Any empirical research on the evolution of morphological characters has to be based on some idea of what the units of evolution are and what constitutes something new as compared to a modification of a preexisting character. The basic assumption of our research is that the question of what is an evolutionary novelty (what is new?) is the exact complement of the question of homology (what is the same?) (Müller and Wagner 1991). The goal of the conceptual work, which began with papers on the so-called "biological homology concept" (Wagner 1989a; Wagner 1989b), is to make these difficult concepts precise enough to stimulate and guide empirical research (Wagner 1999). Digit homology The question of whether the three digits of the avian hand correspond to the first second and third digit of the pentadactyl hand or to the digits two, three and four, has occupied morphologists, paleontologists and developmental biologists for well over one century. The present project attempts to resolve this question from a developmental point of view. Recognizing that there are basically only two competing hypotheses, the so-called axis shift hypothesis (Chatterjee 1998), and the frame shift hypothesis (Wagner and Gauthier 1999), we attempt to find empirical evidence to discriminate between them. Recent evidence shows that the anterior most digit in the chicken wing has the same Hox gene expression pattern as the first digit in the mouse and the alligator (Vargas et al., 2008). This shows that in the chicken wing a digit 1 is developing in the place that normally gives rise to digit 2, as predicted by the frame shift hypothesis. Furthermore, we found that character identity shifts can be induced experimentally in the chicken wing by a chemical knock down of Sonic hedgehog signaling (Vargas and Wagner 2009). These data provides cues to search for the genetic basis for the avian digit identity frame shift (current work by Drs Rebecca Young and Zhe Wang). Moreover, recent evidence suggests that the frame shift hypothesis also explains the apparent discrepancy between the identity of the anterior-most digit in embryonic and adult Chalcides chalcides, a scincid lizard (Young et al., 2009). Our ongoing work exploring the ancestral developmental patterning of the Chalcides hand seeks to confirm this (current work by Drs Matthew Brandley and Rebecca Young). The evolution of transcription factor function Through our work on the molecular evolution of transcription factor genes (e.g. Chiu et al., 2001; Lynch et al., 2004; Wagner et al., 2005; Crow et al., 2006, 2009) we became interested in the role of transcription factor protein change in the evolution of transcriptional control. This concerns the question whether transcription factor proteins are in fact the unchanging building blocks of gene regulation, as assumed in the dominant paradigm of gene regulatory evolution, or whether protein evolution plays a causal role in the evolution of gene regulation. A survey of the literature shows that there is no doubt that transcription factor proteins change during evolution in a functionally relevant way (see Lynch and Wagner 2008; Wagner and Lynch 2008). The question rather is what is the biological role of these transcription factor changes? Through our work on the evolution of gene regulation in endometrial stromal cells (see below), we found that transcription factor protein changes are likely to be associated with and may be even instrumental in the origin of evolutionary novelties, such as new cell types (see Lynch et al., 2008, PNAS). Hence we think that in fact, and consistent with the cis-regulatory paradigm, most gene regulatory changes are due to nucleotide substitutions in existing enhancers and promoters. But in the context of evolutionary transformation that require the evolution of novel functional specificities of transcription factors novel protein-protein interaction arise, necessitating the evolution of the transcription factor proteins themselves. We are aware that this is still a poorly tested hypothesis but our research focus is to investigate the biochemical changes that are associated with adaptive amino acid substitutions in transcription factors. The evolution of gene regulatory networks We assume that the evolution of novel morphological characters boils down to the evolution of a novel gene regulatory networks that control the developmental identity of a cell type, an organ rudiment or a tissue type. Hence we are interested in the genetic mechanisms that lead to large scale re-wiring of transcriptional control networks in cells. In our lab the paradigm for studying these processes is the evolution of the endometrial stromal cells of placental mammals. Studying gene regulation in endometrial stromal cells led us to the idea that two factors are particularly important for the origin of novel gene regulatory networks: 1) the origin of novel cis-regulatory elements (TE) from transposable elements, and 2) the co-adaptation among transcription factor proteins by adaptive amino acid substitutions (see also above). 1) The idea that TE may play a major role in the evolution of gene regulatory networks is old (e.g. Britton and Davidson 1981), but only recently with the availability of genomic data has broad based support for this idea emerged. We aim at tracing the contribution of TE to the gene regulatory network of endometrial stromal cells (current work by Drs Vincent Lynch, Kathryn Brayer and Mauris Nnamani, and Deena Emera). 2) The functional specificity of transcription factor critically depends on their interaction with other transcription factor proteins via protein-protein interactions, in addition to binding to the DNA. For the evolutionary geneticist this implies that the evolution of novel functional roles of transcription factors is possibly caused by the evolution of novel protein-protein interactions. In support of this idea we have shown that during the recruitment of HoxA11 into regulating genes during endometrial stromal cell differentiation (aka decidualization) the protein underwent adaptive modification. These changes led to novel functional activities in regulating decidual genes, like prolactin, that can not be done by the ancestral HoxA11 protein, or the protein from any other non-placental animal (Lynch et al., 2008 and 2009). This proofs that transcription factor proteins can undergo functionally important changes and that these changes are likely to be associated with the origin of novel functional roles for the transcription factor protein. Current research aims at testing whether other transcription factor proteins important for decidualization also underwent functional changes during the evolution of placental mammals (e.g. Foxo1A, C/EBP-b ETS1 etc) (current work by Drs Vincent Lynch and Mauris Nnamani). We are also interested in the biochemical mechanisms for the derived ability of placental HoxA11 protein to regulate PRL, but not the HoxA11 of non-placental animals. In this research we aim at tracing the evolution of protein-protein interactions among transcriptional regulators (work by Dr Kathryn Brayer), and how the adaptive amino acid substitutions have affected the structure of HoxA11 and its protein interactions (collaboration with Jens Meiler and Laura Mizoue, Vanderbilt University