The path from the discovery of a gene involved in mental retardation (MR) to understanding the mechanism of its functions often follows a similar process requiring each of the specialties of the sub cores. Following the initial identification of the responsible gene, a mouse knock in and/or knock out model is generated. If human disease causing mutations are known, transgenesis of these mutations may be used to determine whether similar etiology may be inferred from the mouse model. In parallel with the other research activities, each of the gene expression sub cores are engaged in the sequential process of discovery. In situ hybridization is used to determine the normal distribution pattern of RNA from the gene, particularty in the mouse brain. The in situ core is able to provide comprehensive analysis of the normal, knock out or transgenic mouse brain RNA distribution pattern in a format that allows precise comparison with the distribution pattern of other known genes. Since the in situ core produces data and images that are directly comparable with the major mouse atlases currently being made available to researchers, the overall data resource is robust and rapidly expanding. Detailed analysis of the pathology of the knockout or transgenic mouse brain is supported by the neuorpathology core. Here brain and other tissue samples are examined by specialists using conventional histology and immunohistochemistry often leading to a detailed understanding of the specific abnormalities. The confocal microscopy core facilities are used to prepare physically and/or optically sectioned samples used to study protein distribution, to compare normal and abnormal patterns of distribution, to determine whether other proteins are affected by the gene and to study the three dimensional distribution of the gene product. Very often the linear pattern of discovery described is an extreme oversimplification and the actual process is iterative because the results of one core both inform and are informed by the results of another. This is one of the key benefits of engaging the several cores in long term collaborative arrangements. Among the long term studies relevant to IDD that have benefited from the above processes through the BCM-IDDRC gene expression core are Rett Syndrome (Zoghbi lab), forms of Fragile X (Nelson lab), and Angelmen syndrome (Beaudet lab), SCA1 (Zoghbi, Bellen, Botas labs). As an example, alteration of the MeCP2 gene as the primary genetic basis of Rett syndrome was discovered by the Zoghbi laboratory in 1999 following more than a decade of collaborative work on the disease spanning many disciplines including clinical observations, pathology, analysis of behavior and molecular biology (1) . Throughout this period the pathology core provided invaluable support through histology, identification and analysis. More recently, the confocal microscopy core and the in situ core have come to play a significant role in studying the relationship of MeCP2 to other proteins, the effects of X linkage in Rett and the mechanisms of Mecp2 function. Work during the current grant period has gradually been unraveling individual components of the wide range of abnormalities associated with Rett but has focused particularly upon aspects of the disease that may be susceptible to remediation. Unusual susceptibility to stress is a hallmark of Rett syndrome and an elevated stress response is also present in mice models with an truncated MeCP2 transgene (2) . In support of the Zoghbi lab' efforts to study the stress response of these mice the in situ core provided histology and statistical analysis demonstrating that the CrH gene is elevated in regions of the brain associated with corticosteroid release (2) . Continuing with this information, the Zoghbi laboratory found that regulatory elements of the CrH promoter region interact directly with MeCP2 but do not bind the MeCP2(308) truncated gene. Using a Cre-loxP technology, MeCP2 was then eliminated exclusively from Sim-1 expressing hypothalamic cells reproducing the abnormal stress response found in mice lacking MeCP2(3) . Results from the In situ core and confocal microscopy core were then used to determine that these conditional knock out mice have reduced expression of MeCP2 in the same stress response associated regions in which MeCP2 is under-expressed in Mecp2 (308) mice and that stress response related genes such as glucocorticoid-inducible kinasel and FK-506-binding protein are mis-regulated in the Mecp2 null brain. The potential for accurate clinical diagnosis is complicated in X-linked diseases such as Rett because X chromosome inactivation (XCI) may be skewed by genetic and epigenetic factors to mask phenotypic expectations. Work by the Zoghbi laboratory, motivated by prior clinical evidence of imbalanced XCI in some human Rett patients and high phenotypic variability in some mouse models of Rett, employed the confocal core facilities for detailed analysis of XCI at the cell and tissue levels in Mecp2 (308) mice (4) . Using an antibody that recognized wild type MeCP2 but not MeCP2(308) together with antibodies that recognize specific neurons, it could be shown that XCI is skewed throughout the brain in Mecp2(308)/X mice and that in Mecp2(308) mice the degree of skewing toward the wild type genetic background observed at the cellular and tissue level was inversely correlated with the penetrance of mutant phenotypes. The importance of precise regulation of Mecp2 expression was explored in studies comparing neuronal function in mouse neurons where MeCP2 is over-expressed or under-expressed (5) . In this study the confocal microscopy core equipment was used to correlate synapse density with synapse function and to confirm that MeCP2 is involved in early postnatal synaptogenesis and maintenance of glutamatergic neurons in vitro and in vivo. This work has important implications because it provides evidence for the early role of synaptogenesis in IDD generally and because it offers another avenue for therapeutic intervention.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Center Core Grants (P30)
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Baylor College of Medicine
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