The gene regulatory network controlling proximal limb development in mice

在发育中的胚胎中形成特定结构（胚胎模式）需要细胞通过分泌信号进行交流，这些信号从一个细胞扩散到另一个细胞。通常这些信号是蛋白质。每个细胞的基因都含有这些信号蛋白的DNA编码。这些基因必须由另一种叫做转录因子的蛋白质精确地开启和关闭。转录因子与基因附近的DNA结合，调节基因的转录方式。转录是指从DNA序列的编码中产生RNA然后RNA被翻译成蛋白质的过程。因此，研究发育的最大挑战之一是了解编码信号蛋白的基因如何在特定细胞中被转录因子打开，以及信号蛋白如何指导特定结构的发育。***在短期内，我们关注胚胎模式系统的单个组件，以便我们以后可以将这些模块安装到一个更大的系统中。因此，我们的长期目标是了解基因如何组织成更复杂的系统，称为基因调控网络。在这种背景下，我的实验室研究了转录因子SHOX2的发育功能，该转录因子是由矮小同型盒基因2 （SHOX2）编码的。SHOX2是理解转录因子如何控制发育的一个极好的模型，因为它在包括四肢、上颚和心脏在内的各种发育结构中具有重要功能。我们主要研究了SHOX2如何控制肢体特定骨骼的发育。我们发现，当Shox2基因在四肢发育过程中失活（“敲除”）时，手臂和腿部的肱骨和股骨实际上分别被删除了。在目前的建议中，我们使用遗传学（将不同种类的突变小鼠交配）来确定不同基因如何共同作用形成肢体。我们还建议在四肢的不同细胞中，在不同的时间灭活Shox2，以找出其功能重要的时间和地点。最后，我们还比较了来自不同种类突变小鼠肢体的mRNA，以帮助确定哪些基因在控制肱骨和股骨发育的基因调控网络中受到调控。

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.