Associate Professor One of the major challenges in neurobiology is understanding the cellular and molecular mechanisms underlying development of the vertebrate central nervous system (CNS). Research in our laboratory seeks to elucidate these mechanisms by studying development of the vertebrate forebrain and visual system. We study these systems by taking advantage of mutations that affect development of the brain and eye in humans, mice, and zebrafish. Because genetic approaches do not rely on previous assumptions, details about the mechanisms mediating development of the visual system and forebrain can be uncovered that might not be identifiable using other means. Genes involved in eye development We are currently studying aniridia in humans and the Small eye trait in rodents. Aniridia is a congenital inherited malformation of the eye that occurs in approximately one-in-sixty-thousand babies each year. Individuals afflicted with this disease typically feature severe hypoplasia of the iris and may have associated defects including corneal opacification, cataracts, and hypoplasia of the ciliary body and retina. This combination of ocular defects results in poor visual acuity early in life and can lead to blindness. Small eye is the mouse model for aniridia. Aniridia and Small eye are caused by mutations in the PAX6 gene. PAX6, a paired-box transcription factor, is important for development of the eye, forebrain, and subsets of neurons within the brain and spinal cord. Heterozygous loss-of-function PAX6 mutations cause eye malformations in mammals. Homozygous mutations result in absence of the eyes and nose, loss of forebrain structures, disruption of axon tracts, abnormal neuronal migration, and misspecification of neurons. Although mutations in the PAX6 gene cause aniridia, there are cases in which the PAX6 gene is unaffected. We have identified a novel gene, tentatively named La Femme d' Cot (LFDC), that is disrupted in some of these cases. We subsequently identified this gene in rodents, zebrafish, Drosophila, and C. elegans. In mice, Lfdc is expressed both in the developing eye and in discrete domains within the developing CNS. This expression pattern suggests that, like Pax6, Lfdc may have multiple roles in neural development, although its molecular function is unknown. We are currently investigating the role of Lfdc during embryonic development. Identifying genes downstream of PAX6 Although Pax6 is important for several aspects of CNS development, little is known about the identity of the genes that are regulated by Pax6 genes likely to be important for development of the eye and forebrain. To identify such genes, we have created libraries likely to contain genes regulated by Pax6 and are currently testing candidate clones. This work is being conducted in collaboration with Drs. Nadean Brown (Northwestern University Medical School) and Grant Mastick (University of Nevada, Reno). Zebrafish: A useful vertebrate for studying early brain development Zebrafish embryos are well-suited for detailed studies of the mechanisms underlying development of the forebrain because they develop rapidly, are transparent, and have a relatively simple, extensively characterized nervous system. These characteristics facilitate visualization of developing brain regions, including specific neurons and their axons, in both living and histologically prepared embryos. Additionally, zebrafish embryos can be manipulated experimentally by ablation or transplantation of a single or a small group of cells and genetically by both mutagenesis and by the generation of transgenic animals. Our long-term goal is to develop therapies that can correct genetic and acquired damage to the CNS. Understanding the basic developmental mechanisms by which this system is formed and maintained will provide the insights necessary for obtaining this goal. Research Programs: Cells and Disease Cells in Development Research Interests: Developmental neurobiology: molecular genetic mechanisms of vertebrate eye and forebrain development Selected Publications Sornborger, A.T., Broder, J., Majumder, A., Srinivasamoorthy, G., Porter, E., Reagin, S.S., Keith, C., and J.D. Lauderdale. (2008) Estimating weak ratiometric signals in imaging data. II. Meta-analysis with multiple, dual-channel datasets. J. Opt. Soc. Am. A. 25(9):2185-2194. Kim, J. and J.D. Lauderdale. (2008) Overexpression of pairedless Pax6 in the retina disrupts corneal development and affects lens cell survival. Dev. Biol. 313:434-454. Fan, X., Majumder, A., Reagin, S.S., Porter, E.L., Sornborger, A.T., Keith, C.H and J.D. Lauderdale. (2007) New Statistical Methods Enhance Imaging of Cameleon FRET in Cultured Zebrafish Spinal Neurons. J. Biomedical Optics 12(3):034017. (Selected for inclusion in the June 1, 2007 issue of Virtual Journal of Biological Physics Research) Broder, J., Majumder, A., Srinivasamoorthy, G., Porter, E., Keith, C., Lauderdale*, J.D. and A.T. Sornborger*. (2007) Estimating weak ratiometric signals in imaging data I: dual-channel data. J. Opt. Soc. Am. A, 24(9):2921–2931. *Lauderdale and Sornborger are co-Senior Investigators on this project. Lakowski, J., Majumder, A., and J.D. Lauderdale. (2007) Mechanisms controlling Pax6 isoform expression in the retina have been conserved between teleosts and mammals. Dev. Biol. 307:498-520. Kim, J. and J.D. Lauderdale (2006) Analysis of Pax6 expression using a BAC transgene reveals the presence of a paired-less isoform of Pax6 in the eye and olfactory bulb. Dev. Biol. 292:486-505. Lauderdale, J.D., Wilensky, J.S., Oliver, E.R., Walton, D.S., and T. Glaser. (2000) 3' deletions cause aniridia by preventing PAX6 gene expression. Proc. Nat. Acad. Sci. 97(25):13755-13759. Lauderdale, J.D., Pasquali, S. K., Fazel, R., van Eeden, F. J. M., Schauerte, H. E., Haffter, P, and J.Y. Kuwada. (1998) Regulation of netrin-1a expression by hedgehog proteins. Mol. Cell. Neuro. 11(4):194-205. Lauderdale, J.D., Davis, N.M., and J.Y. Kuwada. (1997) Axon tracts correlate with netrin-1a expression in the zebrafish embryo. Mol. Cell. Neuro. 9(4): 293-313. Liu, K., Lauderdale, J.D., and A. Stein. (1993) Signals in chicken b-globin DNA influence chromatin assembly in vitro. Mol. Cell. Biol. 13(12):7596-7603. Lauderdale, J.D. and A. Stein. (1993) Effects of plasmid length and positioned nucleosomes on chromatin assembly in vitro. Biochemistry 32(2):489-499. Lauderdale, J.D. and A. Stein. (1992) Introns of the chicken ovalbumin gene promote nucleosome alignment in vitro. Nucl. Acids Res. 20(24):6589-6596. Jeong, S.-W., Lauderdale, J.D., and A. Stein. (1991) Chromatin assembly on plasmid DNA in vitro: apparent spreading of nucleosome alignment from one region of pBR327 by histone H5. J. Mol. Biol. 222(4):1131-1147.