The gene regulatory network controlling proximal limb development in mice

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The formation of specific structures in a developing embryo (embryonic patterning) requires that cells communicate by secreting signals that diffuse from one cell to another. Usually these signals are proteins. The genes of each cell contain a DNA code for these signalling proteins. These genes must be turned on and off precisely by other proteins called transcription factors. Transcription factors bind to DNA near genes to regulate how they are transcribed. Transcription is the process by which RNA is produced from the code of the DNA sequence and then RNA is then translated into proteins. Therefore, one of the biggest challenges of studying development is understanding how the genes that code for signalling proteins are turned on in specific cells by transcription factors and how the signalling proteins then direct the development of specific structures. In the short-term we focus on individual components of the embryonic patterning system so that we can later fit these modules into a larger system. Therefore, our long-term goal is to understand how genes are organized into more complex systems called gene regulatory networks. Within this context my laboratory studies the developmental function of the transcription factor SHOX2, which is encoded by the short stature homeobox gene 2 (Shox2). SHOX2 is an excellent model for understanding how a transcription factor controls development because it has an important function in a variety of developing structures including the limbs, palate, and heart . We have primarily studied how SHOX2 controls the development of specific bones of the limbs. We found that the humerus and femur of the arms and legs respectively are virtually deleted when the Shox2 gene is inactivated ("knocked out") during the development of the limbs. In the current proposal we use genetics (mating different kinds of mutant mice together) to determine how different genes work together to form limbs. We also propose to inactivate Shox2 in different cells in the limbs and at different times to tease apart when and where its function is important. Last, we also compare the mRNA from the limbs of different kinds of mutant mice to help determine which genes are regulated within the gene regulatory network that controls the development of the humerus and femur.