Pachnis group ::

Development of the Mammalian Nervous System

Extracellular signalling molecules and their cell surface receptors, intracellular biochemical pathways and nuclear transcription factors are part of signalling cascades that control selective survival, migration, differentiation and proliferation of neuronal and glial progenitors during neurogenesis. To understand the molecular control of such processes we have been studying the development of the largest subdivision of the mammalian peripheral nervous system, the enteric nervous system. The enteric nervous system is composed of a vast number of neurons and glia that are grouped into interconnected ganglia, arranged radially throughout the length of the gut wall. The progenitors of enteric neurons and glia originate at the posterior cranial neural crest which, upon entering the foregut, migrate in a rostrocaudal direction to colonise its entire length. Failure of complete colonisation of the gut by neural crest cells during embryogenesis results in partial or complete absence of enteric ganglia, the most common cause of congenital intestinal obstruction in humans (Hirschsprung's disease). Several studies over the past decade have identified some of the signalling molecules that play a critical role in the development of the enteric nervous system. Among these are the glial-cell line derived neurotrophic factor (GDNF) and its receptor tyrosine kinase RET which have been documented to play an important role in enteric neurogenesis.

One of our research goals is to understand the molecular basis of enteric neurogenesis in vertebrates and to achieve it, we have been taking a multifaceted approach. Given the critical role of the GDNF/RET signalling pathway in enteric nervous system development, we have been exploiting molecular embryological techniques to generate mouse strains expressing mutant forms of the RET receptor. The aim of these studies is to identify critical regions of the receptor, gain insight into the specific signalling pathways it normally activates and generate mouse models of human diseases associated with RET mutations. We are using some of these mutants to study the genetic interaction of Ret with other genes that are also important for enteric nervous system development and employ a variety of in vitro and in vivo assays to study the molecular basis of such interactions. As part of our efforts to understand the molecular basis of cellular divergence and complexity in the enteric nervous system, we are undertaking genome-wide approaches to systematically search for genes that are expressed by and are important for the specification and differentiation of the progenitors of the enteric nervous system. To understand the function of such genes at the cellular level, we have devised methods to isolate and study in culture multilineage progenitors of enteric neurons and glia. We are interested in understanding the mechanisms that control self-renewal and differentiation in these progenitors and use them as a paradigm for rescuing the enteric neuronal deficiencies in animal models of Hirschsprung's disease.

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One of the challenges in neurobiology is to understand the molecular mechanisms controlling the development and function of the forebrain, the most complex part of the nervous system and the site of sensory, motor and cognitive functions. Recent studies have shown that members of the LIM-Homeodomain family of transcription factors play a crucial role in the differentiation, migration and axonal growth of various neuronal subtypes. Consistent with a role of this gene family in forebrain development, we have identified two novel LIM-Homeodomain protein encoding genes, Lhx6 and Lhx7, which are expressed in restricted neuronal subsets of the basal ganglia and the cortex. We are using gene expression studies to map in detail the neuronal cell populations expressing the Lhx6 and Lhx7 genes in the forebrain of mouse embryos. In addition, we are using gene inactivation, reporter integration and gain-of-function approaches in mice to dissect the role of these genes in the differentiation of the various neuronal subclasses of the forebrain. The goal of our studies is to contribute to the understanding of the molecular and cellular mechanisms underlying the generation of neuronal diversity and patterning in the mammalian forebrain during embryogenesis.

Taken together, our developmental studies on experimental paradigms from the mouse central and peripheral nervous system will provide insight into the processes by which extrinsic and intrinsic cell mechanisms cooperate to generate appropriate neuronal cell diversity at the correct stage and positions to allow the formation of functional neuronal networks.

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