QTL mapping of cell number in the mouse CNS
Informatics Center for Mouse Genomics
Multi-level functional studies of candidate dyslexia susceptibility genes in the rat
Funded Projects of the Rosen Lab
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QTL mapping of cell number in the mouse CNS |
Informatics Center for Mouse Genomics |
Multi-level functional studies of candidate dyslexia susceptibility genes in the rat |
The cerebral cortex plays an essential role in the integration of higher cognitive functions, while the striatum is intimately involved in the coordination of movement and executive function. A variety of developmental disorders have been associated with perturbations of these anatomic regions, including developmental dyslexia, autism, schizophrenia, Tourette's syndrome, and bipolar disorders to name but a few. This proposal seeks to map quantitative trait loci (QTL) that modulate absolute and relative magnitudes of glial and neuronal cell numbers and regional volume in both the neocortex and striatum of the mouse. Using a genetic reference population, classic QTL mapping techniques, bioinformatic haplotype mapping, and microarray analysis of gene expression profiles, a small but important set of genes that are responsible for some of the remarkable quantitative differences seen among inbred strains of mice will be mapped. The following questions will be addressed:
To answer these questions, highly accurate, unbiased, and efficient estimates of cell number and volume will be assessed by stereology. These traits will be mapped using GeneNetwork, a public online resource for the investigation of systems genetics. The QTL intervals thus defined will be narrowed using haplotype maps derived from sequence databases of the two parent strains, and by the creation of a database of gene expression levels of the BXD recombinant inbred set at different stages of development. All data gathered from these experiments will be added to GeneNetwork and will be publicly accessible. The questions addressed in the proposal have important implications for a number of disease states, including a variety of developmental disorders. The extension of current transcriptome databases to encompass gene expression analysis at various stages of development will enable a systems genetic approach to understanding fundamental aspects of brain development.
The purpose of this Human Brain Project is to develop and enhance a suite of Web accessible resources and analytic tools that are being used to study the underlying genetic bases for molecular, structural, and functional variation of the CNS. Our resources include extensive digital image repositories, massive transcriptome data sets, and two decades worth of legacy phenotype data that are completely open to the research community through web sites at nervenet.org, mbl.org, www.webqtl.org, and www.neuroterrain.org. The Informatics Center for Mouse Neurogenetics provides a unique research environment for exploring and synthesizing complex data sets across scales—from SNP polymorphisms and variation in gene expression, through to neuroanatomical, cellular, physiological, and behavioral traits. We rely on an essentially immortal reference panel that consists of 80 BXD recombinant inbred strains generated by crossing mouse strains that have both been sequenced. We will extend four significant resources and technologies:
The Mouse Brain Library (MBL) consists of a large digital library of images suitable for online structural and stereological analysis of the CNS. Images can be rapidly searched, sorted, and downloaded at a resolution of 0.2–5.0 microns per pixel using an intuitive and powerful Web interface. This project is the responsibility of the Rosen Lab.Achieving the aims of these four projects will catalyze a new approach to studying the nervous system and will lead to novel lines of research on the development, normal function, and disease mechanisms that affect the human brain.
The aims of this project iis to study a unique rat model of developmental learning disability that uses methods of developmental neurobiology, structural anatomy, and behavior to analyze the functions of three candidate dyslexia susceptibility genes (CDSGs). Neuropathologic studies in human dyslexic brains and previous animal models have underscored the importance of focal neuronal migration defects and developmental plasticity for some of the dyslexic deficits. The discovery of CDSGs challenges us to analyze the effects of this genetic variation on brain development, structure, and behavior with respect to learning disability. Using an in utero electroporation method developed in our laboratories, we will transfect into young neurons in the ventricular zone short hairpin RNAs or over-expression constructs targeted against homologs in the rat of CDSG Dyx1c1, Kiaa0319, or Dcdc2. We have already seen that this procedure leads to abnormal neuronal migration, alters neuronal morphology, and causes secondary effects in untouched neighboring neurons, thus producing a picture reminiscent of dyslexic brains. Interesting behavioral alterations are also seen. Project I (J.J. LoTurco, PI) will analyze Dyx1c1's interaction with genes with known molecular pathways involved in process extension, nuclear movement, and cell adhesion, the domains on the Dyx1c1 critical to function. Project II (A.M. Galaburda, PI) will characterize anatomic changes (cortical architecture, cell identity, morphology, and connectivity) associated with knockdown or overexpression of CDSGs. Project III (H. Fitch, PI) will uncover behavioral consequences of CDSG disruption (auditory processing and learning), and will attempt to ameliorate the effects of these genetic manipulations by behavioral interventions. The three interactive projects will be supported by an Administrative Core, an In Utero Electroporation Core, and a Neurohistology, Morphometry, and Data Processing Core. A better understanding of the functions of CDSGs will shed a broader light on mechanisms of normal brain development and on the abnormalities seen in developmental dyslexia, but also offering the possibility of earlier detection, biologically-based subtyping, and improved treatment.