Project Funding Details

We are investigating the molecular mechanisms that control the correct formation and positioning of different nerve cell types in the spinal cord of vertebrates. The assembly of functional neuronal circuits begins in vertebrates with the generation of distinct classes of neurons at defined positions. We have focused on the ventral neural tube, the region of the spinal cord that contains motor neurons and other neuron types that control and coordinate motor output, these neurons allow us to do such things as move our limbs, breath and swallow. Our goal is to understand the molecular mechanisms controlling the pattern in which these distinct neuronal subtypes are generated. An understanding of this processes will have implications for diseases such as motor neuron disease as well as tumours of the nervous system. We have shown that a signalling molecule, Sonic Hedgehog (Shh), plays a central role. Shh is secreted by a defined group of cells at the midline of the neural tube and acts directly on neural cells throughout the ventral neural tube. Shh signalling controls, in a concentration dependent manner, the expression of a group of homeodomain proteins in neural progenitors. The combinatorial expression of these homeodomain proteins establishes five distinct domains of progenitors. Homeodomain proteins expressed in adjacent domains cross-repress each other's expression refining and maintaining progenitor domains and, as cells differentiate, the homeodomain proteins expressed in a progenitor domain direct neuronal subtype identity. While these data begin to reveal the genetic networks that interpret Shh signalling to control neuronal fates, the way in which the graded activity of Shh signals intracellularly to control gene expression is poorly understood. The control of differential gene expression by a graded signal is a central question in developmental biology and similar issues have arisen from the study of the development of other embryonic tissues. To address this problem in the neural tube, we are taking a combination of molecular, cellular and embryological approaches. Using in vivo transgenic methods in mouse and chick embryos, we are examining how components of the Shh signalling pathway including Shh regulated transcription factors control gene expression. Conversely, we are identifying the DNA elements necessary to control Shh regulated genes. In parallel we are developing Shh responsive cell lines to allow the in vitro characterisation of Shh signalling. These approaches together with the reagents available and the level of knowledge we have of the developing nervous system should allow us to provide answers to how a graded signal regulates gene expression. In addition, Shh signalling is important in the development of other tissues, including limbs and the skin, it is likely therefore that this research will increase our understanding of a number of congenital birth defects as well as cancers such as basal cell carcinoma and medulloblastoma. Graded Shh signalling alone is not sufficient to account for the variety of neuronal subtypes generated in the ventral neural tube, indicating that additional mechanisms increase neuronal diversity. Using the strategy of examining candidate regulators and target genes we are analysing situations in which mechanisms other than Shh signalling must play a role in specifying neuronal subtype identity. Together, these approaches will provide an understanding of the mechanisms controlling neural tube development. Keywords: Vertebrate embryonic development. Neural development. Cell-Cell signalling. Molecular Biology. Spinal Cord.