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Research Summary
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 autism. Thus, the discovery of the mechanisms by which the cerebellum is formed is of interest to both basic and clinical science. We have recently described the first genes causing Dandy-Walker malformation, the most common birth defect of the cerebellum in humans. Infants with this disorder, which occurs in about one in 10,000 births, often have reduced coordination, impaired mental function and hydrocephalus. By studying patients with deletions of chromosome 3q, we showed that heterozygous loss of the linked ZIC1 and ZIC4 genes causes Dandy-Walker malformation and we created mouse models to study the developmental basis of the disorder and identify interacting genes. We have identified several other loci and are searching for additional causative genes. In parallel, we are studying mutant mice with cerebellar developmental malformations to identify other genes and developmental mechanisms regulating cerebellar development. For example, in dreher (Lmx1a-/-) mice, the roof plate, an important dorsal signaling center in the developing CNS, is missing. As a result, neurons along the entire dorsal CNS, including the cerebellum, are inappropriately patterned and differentiate abnormally. Other mouse cerebellar developmental mutants are also currently under study in the lab and we are using expression analysis, fate mapping, genetic and chick electroporation assays to assess mechanisms of cerebellar formation. 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.

Selected Publications

Millen, K.J. and Gleeson, J. (2008) Cerebellar development and disease. Current Opinion in Neurobiology, 18:12–19

Millen, K. J., Grinberg, I., Blank, M. and Dobyns, W. B. (2008). ZIC1, ZIC4 and Dandy-Walker malformation. In Inborn Errors of Development, 2nd edition (ed. C. J. Epstein R. P. Erickson and A. Wynshaw-Boris). Oxford: Oxford University Press.

Elsen, G.E., Choi, L., Millen, K.J., Grinblat, Y. and Prince, V.E. (2008) Zic1 and Zic4 proteins regulate zebrafish hindbrain ventricle morphogenesis. Dev. Biol.; 314:376-392

Barkovich, J.A., Millen, K.J. and Dobyns, W.B. (2007) A Developmental Classification of Malformations of the Brain Stem. Ann Neurol.; 62:625-39

Chizhikov, V., Davenport, J. Zhang, Q., Shih, E.K., Cabello, O.A., Fuchs, J., Yoder, B.K., and Millen, K.J. (2007) Cilia proteins control cerebellar morphogenesis by promoting granule progenitor pool expansion J. Neurosci.; 27;9780-9789 

Millen, K.J. (2007) Understanding cerebellar patterning. J. Visualized Experiments 9: http://www.jove.com/index/Details.stp?ID=407

Chizhikov, V., Lindgren, A., Monuki, E. and Millen, K.J. (2006) The dorsal midline is a signaling center regulating cerebellar neural cell-type specification and proliferation. Development: 133(15):2793-804

Chizhikov, V. and Millen, K.J (2005). Roof plate–dependent patterning of the vertebrate dorsal central nervous system. Developmental Biology; 277(2): 287-95.

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; 36 (10):1053-5

Chizhikov, V. and Millen, K.J (2004). Mechanisms of roof plate formation in the vertebrate CNS. Nature Reviews Neuroscience; 5(10): 808-12

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. (2004) Control of roof plate formation by Lmx1a in the developing spinal cord. Development;131 (11):2693-705.

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., 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.