Kathleen Millen
Research Summary / Selected Publications
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 and 6p, we have shown that loss of both ZIC1 and Zic4, or loss of FOXC1 genes causes Dandy-Walker malformation. We have used mouse models to study the developmental basis of the disorder and identify interacting genes and novel developmental pathways. We have identified several other loci and are searching for additional causative genes.
In parallel, we are studying several lines of mutant mice with cerebellar developmental malformations to identify other genes and mechanisms regulating cerebellar development. 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
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 and 6p, we have shown that loss of both ZIC1 and Zic4, or loss of FOXC1 genes causes Dandy-Walker malformation. We have used mouse models to study the developmental basis of the disorder and identify interacting genes and novel developmental pathways. We have identified several other loci and are searching for additional causative genes.
In parallel, we are studying several lines of mutant mice with cerebellar developmental malformations to identify other genes and mechanisms regulating cerebellar development....
FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation (2009) Aldinger, K.A., Lehmann, O.J., Hudgins, Chizhikov V.V., Bassuk, A.G., Ades, L.C., Krantz, I.D., Dobyns,W.B and Millen, K.J. Nature Genetics (in press)
Aldinger, K.A., Sokloff, G., Rosenberg, D., Palmer, A.A. and Millen, K.J. (2009) Genetic variation and population substructure in outbred CD-1 mice: implications for genome-wide association studies. PLoS ONE 4(3): e4729.
Millen, K.J. and Gleeson, J. (2008) Cerebellar development and disease. Current Opinion in Neurobiology 18:12-19
Millen, K.J. (2007) Understanding cerebellar patterning. J. Visualized Experiments 9: http://www.jove.com/index/Details.stp?ID=407 LINK TO VIDEO
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
Chizhikov, V., Lindgren, A., Currle, D., Rose, M., 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
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) 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 (2004). Mechanisms of roof plate formation in the vertebrate CNS. Nature Reviews Neuroscience; 5(10): 808-12
Chizhikov, V. and Millen, K.J. (2003) Development and malformations of the cerebellum in mice. Molecular Genetics and Metabolism.80: 54-65.
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)
FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation (2009) Aldinger, K.A., Lehmann, O.J., Hudgins, Chizhikov V.V., Bassuk, A.G., Ades, L.C., Krantz, I.D., Dobyns,W.B and Millen, K.J. Nature Genetics (in press)
Aldinger, K.A., Sokloff, G., Rosenberg, D., Palmer, A.A. and Millen, K.J. (2009) Genetic variation and population substructure in outbred CD-1 mice: implications for genome-wide association studies. PLoS ONE 4(3): e4729.
Millen, K.J. and Gleeson, J. (2008) Cerebellar development and disease. Current Opinion in Neurobiology 18:12-19
Millen, K.J. (2007) Understanding cerebellar patterning. J. Visualized Experiments 9: http://www.jove.com/index/Details.stp?ID=407 LINK TO VIDEO
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
