IBN-9816896; JONES, Frederick Cell adhesion molecules (CAMs) play an important role in organizing cells and their interconnections during development of the nervous system. Alterations in the expression of CAMs accompany a number of developmentals abnormalities. Understanding factors that regulate the genes for these molecules would further define their role in neural development. A rich network of regulatory controls is responsible for neural patterns of CAM expression. In this proposal, Dr. Jones will examine the expression of a particular CAM called L1. Mutations in the L1 gene produce aberrant brain development linked to syndromes that include X-linked spastic paraplegia, X-linked hydrocephalus and mental retardation, and agenesis of the corpus collosum. In preliminary experiments, the regulatory region of the L1 gene including its promoter was identified and characterized. The two DNA regulatory elements that were critical for its expression in the nervous system were determined. These include a neuron-restrictive silencer element (NRSE) which prevents L1 expression in non-neural tissues and a binding site (HPD) for transcription factors of the homeobox and Pax families which is necessary for expression of L1 in the central nervous system. The HPD is also necessary for induction of L1 expression by an important family of growth factors, the bone morphogenetic proteins (BMPs). In this proposal, the nature of the protein factors that bind to the HPD and control L1 expression during neural development will be determined. Specific factors that are responsible for regulation of L1 expression by BMP2 and BMP4 in neural and non-neural cells will be identified and it will be determine whether the NRSE and its binding factor REST/NRSF impede BMP activation of L1 expression in non-neural cells. Finally, the role of the HPD during neural development will be examined in a number of ways. The expression patterns of L1 transgenes containing and lacking the HPD will be compared in different transgenic mice. BMP2, BMP4, their receptors (BMPR-I and BMPR-II) will be localized along with the particular homeobox and Pax transcription factors that bind to and regulate L1 expression via the HPD. Such experiments will help provide insight into the cellular contexts in which BMP signaling and transcriptional control by homeobox and Pax proteins regulate L1 expression in vivo. Overall, the results from these experiments should provide a connection between an important family of extracellular signalling molecules, transcriptional regulators that are known to control regional patterns of neural differentiation, and the process of neural cell adhesion.
