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Molecular and Cellular Biology, September 2002, p. 6636-6647, Vol. 22, No. 18
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.18.6636-6647.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Dyrk1A Haploinsufficiency Affects Viability and Causes Developmental Delay and Abnormal Brain Morphology in Mice

Vassiliki Fotaki,^1,2 Mara Dierssen,^1,2 Soledad Alcántara,³ Salvador Martínez,⁴ Eulàlia Martí,^1,2 Caty Casas,^1, Joana Visa,^1, Eduardo Soriano,³ Xavier Estivill,^1,2 and Maria L. Arbonés^1,2*

Medical and Molecular Genetics Center, Institut de Recerca Oncològica, 08907-L'Hospitalet de Llobregat, Barcelona,¹ Genes and Disease Program, Centre de Regulació Genòmica, 08003-Barcelona,² Department of Cell Biology and Neuroscience Research Center (CERN), University of Barcelona, 08028-Barcelona,³ Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550-Alicante, Spain⁴

Received 18 April 2002/ Returned for modification 3 June 2002/ Accepted 13 June 2002

DYRK1A is the human orthologue of the Drosophila minibrain (mnb) gene, which is involved in postembryonic neurogenesis in flies. Because of its mapping position on chromosome 21 and the neurobehavioral alterations shown by mice overexpressing this gene, involvement of DYRK1A in some of the neurological defects of Down syndrome patients has been suggested. To gain insight into its physiological role, we have generated mice deficient in Dyrk1A function by gene targeting. Dyrk1A^-/- null mutants presented a general growth delay and died during midgestation. Mice heterozygous for the mutation (Dyrk1A^+/-) showed decreased neonatal viability and a significant body size reduction from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay of Dyrk1A^+/- mice and specific alterations in adults. Brains of Dyrk1A^+/- mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction. These data provide evidence about the nonredundant, vital role of Dyrk1A and suggest a conserved mode of action that determines normal growth and brain size in both mice and flies.

Present address: Aventis-Pharma, 94400-Vitry, France.

Present address: Research Animal Facility, Barcelona Science Park, 08028-Barcelona, Spain.

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