We are interested in development of the cerebellum, the primary center of motor coordination in the CNS. Cerebellar disorders in both mouse and human cause ataxia, tremor and abnormal eye movements. Recent studies in humans have also implicated the cerebellum in cognitive processing deficits and sensory discrimination in multiple medical conditions including pervasive developmental disorders of childhood such as autism. Thus, the discovery of the molecular and cellular mechanisms by which the cerebellum is formed is of interest from both a basic and clinical standpoint.

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
underlying disruptions of brain development during embryogenesis nor is anything known about the genetic basis of the malformation. An understanding of the basis of this common malformation will not only provide valuable, currently unavailable diagnostic information but may also lead to treatments for those with the congenital malformation.

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.

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Selected Publications

Grinberg, I., Northrup, H., Ardinger, H., Prasad, C., Dobyns, W.B. and Millen, K.J. (2004) Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nature Genetics. In Press

Chizhikov, V., and Millen, K.J. (2004). Mechanisms of roof plate formations in vertebrate CNS. Nature Reviews Neuroscience. In Press.

Millen, K.J., Millonig, J.H. and Hatten M.E. (2004) Roof plate and dorsal spinal cord dl1 interneuron development in the dreher mutant mouse. Dev Biol.: 270(2):382-92.

Chizhikov, V. and Millen, K.J. (2004) Control of roof plate formation by Lmx1a in the developing spinal cord. Development;131 (11):2693-705.

Chizhikov, V. and Millen, K.J. (2004) Control of roof plate development and signaling by Lmx1b in the caudal vertebrate CNS. J Neurosci.; 24(25):5694-703.

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.
(* denotes equal contribution)

Millonig J.H.* Millen, K.J.*, and Hatten, M.E. (2000) The dreher gene (Lmx1a) controls formation of the roof plate in the vertebrate CNS. Nature 403:764-769.
(* denotes equal contribution)

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 Hatten, M.E. (1996) A detailed genetic map of the weaver locus on Chromosome 16. Mammalian Genome 7:616-618.

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 York: Wiley-Liss, Inc. pp 339-355.

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.

Davis,, C.A., Holmyard, D.P., Millen, K.J. and Joyner, A.L. (1991). Examining pattern formation in mouse, chicken and frog embryos with an En-specific antiserum. Development 111, 287-298.