Eye, Visual System, and Stereological Analysis of the CNS

P.I. and Contact:   Robert W. Williams, Ph.D.

Lab:   Informatics Center for Mouse Neurogenetics

Location:    Department of Anatomy and Neurobiology, University of Tennessee, Health Science Center, Memphis TN 38163

Description:  We are developing databases, applications, and animal resource as part of a biometric and genetic analysis of the mouse eye and brain. As part of QTL studies we are currently screening several CNS regions for quantitative and morphometric variants. Regions include the hippocampus, cerebellum, thalamus, and the olfactory bulbs, and the striatum (with GD Rosen).

Resources include:

• The Mouse Brain Library: A searchable image database that includes serial section images from over 750 animals and 120 strains, lines, and mutations. The collection also includes QuickTime movies that make it possible to rapidly leaf through collections of serial sections (RW Williams, AG Williams, GD Rosen).
  
  
• Atlas of the Mouse Brain: Complete stereotaxic atlases of C57BL/6J and DBA/2J (Nissl-stained coronal and horizontal sections).
  
  
• Excel and FileMaker databases covering CNS and visual system traits in mice. The database on brain weight includes some coverage of approximately 230 genotypes of mice.
  
  
• The Portable Dictionary of the Mouse Genome: FileMaker and Excel databases lists of 21000 genes and marker loci that you can download and use as part of local mapping and genomics projects.
  
  
• Papers and tutorials with a focus on quantitative genetic studies of visual system and CNS development (Williams and colleagues).

Screening Protocols and Techniques:    We are currently screening mice to find and characterize gene variants that control visual system and CNS development (Williams, 2000). We typically start by screening common inbred strains such as C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ, and A/J, using sensitive and rapid morphometric techniques. We then map genes or quantitative trait loci (QTLs) that generate these differences with recombinant inbred strains and intercrosses. When possible we collect data from five or more animals belonging to each genotype, all older than 30 days. For purposes of positional cloning, gene loci are fine-mapped using advanced intercrosses and high-resolution recombinant inbred intercross (RIX) panels. We are also collaborating with Dan Goldowitz and the Tennessee Mouse Genome Consortium to screen mutations that affect the development of the eye.

Collaborative Interests:  We welcome collaborations, particularly with researchers interested in applying complex trait methods and mutagenesis to study visual system and CNS development. Our research program takes advantage of pre-existing genetic and phenotypic difference amoung strains of mice to map and characterize key modulatory genes. These gene loci are also called quantitative trait loci (QTLs). If you are interested in exploiting complex trait analysis to track down genes that control neuroanatomical, physiological, or behavioral traits in mice please contact Rob Williams at (901) 448–7018.

Selected References

1. Williams RW, Herrup K (1988) The control of neuron number. Annu Rev Neur 11: 423–453. Reprint.
   
   
2. Williams RW, Goldowitz D (1992) Lineage versus environment in embryonic retina: A revisionist perspective. Trends Neurosci 15: 368–373. Reprint.
   
   
3. Williams RW, Hogan D, Garraghty PE (1994) Target recognition and visual maps in the thalamus of achiasmatic mutant dogs. Nature 367:637–639 Preprint.
   
   
4. Williams RW, Strom RC, Rice DS, Goldowitz D (1996) Genetic and environmental control of retinal ganglion cell number in mice. J Neurosci 16: 719–7205. Reprint.
   
   
5. Williams RW, et al. (1998) Genetic dissection of retinal development. Seminars in Cell & Dev Biol 9: 249–255. Reprint.
   
   
6. Williams RW (1998) Neuroscience meets quantitative genetics: Using morphometric data to map genes that modulate CNS architecture. Short Course in Quantitative Neuroanatomy pp. 66–78.Reprint.
   
   
7. Williams RW, Strom RC, Goldowitz D (1998) Natural variation in neuron number in mice is linked to a major quantitative trait locus on Chr 11. J Neurosci 18:138–146.Preprint.
   
   
8. Strom RC, Williams RW (1998) Roles of cell production and cell death in the generation of normal variation in neuron number. J Neurosci 18:9948–9953. Preprint.
   
   
9. Hogan D, Garraghty PE, and Williams RW. (1999) Asymmetric connections, duplicate layers, and reversed maps in the primary visual system. J Neurosci 19:RC38 (1–6).
   
   
10. Zhou G, Williams RW. Eye1 and Eye2: Gene loci that modulate eye size, lens weight, and retinal area in mouse. IOVS 40:817–825. Preprint.
    
    
11. Williams RW (1998) A targeted screen to detect recessive mutations that have quantitative effects. Mamm Gen 10:734–738. Reprint.
    
    
12. Lu L, Airey DC, Williams RW (2000) Genetic architecture of the mouse hippocampus: Identification of loci with specific effects on hippocampal size. Reprint.

Acknowledgements:   Research is supported in part by grants NEI R01EY13070 (an RFA-MH99-006 application), NEI EY12991 (murine myopia models), NINDS NS35485 (complex trait analysis of the retina and CNS), and NIMH P20 MH62009 (Informatics Center for Mouse Neurogenetics; PAR-99-138 and PAR-99-135). I thank my colleagues and collaborators: DC Airey, J Belknap, D Goldowitz, A Kulkarni, L Lu, K Manly, J Nissanov, GD Rosen, RC Strom, L Toth, AG Williams, and G Zhou. James Weber and the NHLBI Mammalian Genotyping Service have been of great help in genotyping our advanced intercross progeny.