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Development of the cerebellum |
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We have chosen to study cerebellar pattern formation in the mouse as a paradigm for human congenital cerebellar malformations. This is based on the hypothesis that similar patterning defects underlie mouse and human malformations. Pattern formation is the term used to describe the emergence of spatial biological organization during development. Several mouse mutants with severe cerebellar defects have been described and attributed to disrupted mechanisms of pattern formation during early embryogenesis. Currently, our work focuses on one such mutant, the dreher mouse. We have demonstrated that the roof plate, an important dorsal signaling center in the developing CNS, is missing in homozygous mutant mice. As a result, neurons along the entire dorsal CNS, including the cerebellum, are inappropriately patterned and differentiate abnormally. We have identified mutations in the Lmx1a gene as the cause of the dreher phenotype. Lmx1a now provides an entry point into the previously unknown molecular pathway of roof plate formation and function. Through use of gene expression arrays and chick electroporation technologies we are defining other genes in the Lmx1a roof plate cascade. Other mouse cerebellar patterning mutants are also currently under study in the lab. We have recently extended our analysis to congenital human cerebellar malformations in an effort to identify further
genes that regulate patterning in the developing CNS. Specifically, we are
studying the genetic basis of Dandy-Walker Malformation Syndrome, a common
congenital cerebellar malformation. Although
common, nothing is understood regarding the By combining the power and strengths of both mouse and human genetics, our
studies will lead to a more comprehensive understanding of the basic biology
and genetics of cerebellar development and will
additionally provide clinically relevant data leading to better diagnosis and
treatment of human congenital cerebellar
malformations. Dandy Walker Research- Please Join our Study Click Here for
details References Chizhikov, V. and Millen, K.J. (2003) Development and malformations of the cerebellum in mice. Molecular Genetics and Metabolism. 80: 54-65. Ramocki, M. B.,* Dowling, J.* , Grinberg, I.* , Kimonis, V. E.,
Cardoso, C., Gross, A., Chung, J., Lese Martin, C.,
Ledbetter, D. H., Dobyns, W. B. and Millen K.J.
(2003). Reciprocal fusion transcripts of two novel Zn-finger genes in a
female with absence of the corpus callosum, ocular colobomas and a balanced translocation between
chromosomes 2p24 and 9q32. European Journal of Human Genetics
11:527-34. Millonig J.H.* Millen, K.J.*, and Millen, K.J., Millonig J.H., Wingate R.J.T., Alder J. and M.E. Hatten. (1999) Neurogenetics of the Cerebellar System. Journal of Child Neurology 14:574-582. Millonig, J.H., Millen, K.J. and Kofuji, P., Hofer, L., Millen, K.J., Millonig, J.H., Lester, H.A. and Hatten, M.E. (1996) Functional analysis of mutant GIRK2 and rescue of weaver granule cells. Neuron 16:941-952. Vogel, M.W., Millen, K.J. and Joyner, A.L. (1996). The Engrailed-2 homeobox gene and patterning of spinocerebellar mossy fiber afferents. Devel. Brain Res.:96:210-218. Gerlai, R., Millen K., Herrup, K., Joyner, A.L. and Roder, J. (1996) Impaired motor learning performance in cerebellar En-2 mutant mice. J. Behav. Neurosci.:110:126-133. Millen, K.J. and Hui, C-C. (1996) Radioactive in
situ hybridization of tissue sections. In: A laboratory guide to RNA;
isolation, analysis and synthesis. P.A. Kreig (ed).New Millen, K.J., Hui, C.-C. and Joyner, A.L. (1995) A role for En-2 and other homologues of Drosophila segment polarity genes in setting up positional information in the developing cerebellum. Development 121:3935-3945. Millen, K.J., Wurst, W.W., Herrup, K. and Joyner, A.L. (1994) Abnormal embryonic and cerebellar development and patterning of post-natal foliation in two mouse Engrailed-2 mutants. Development 120, 695-706. Stroeher, V.L., Kennedy, B.P., Millen, K.J., Schroeder, D.L., Hawkins, M.G., Goszczynski, B. and McGhee, J.D. (1994). DNA-protein interactions in the C. elegans embryo: Oocyte and embryonic factors that bind to the promoter of the gut-specific ges-1 gene. Developmental Biology 163, 367-380. |
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06/25/2004 |