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

Abstract

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.

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

“…In the mnb fly, also phenotypically similar to the human phenotype, efficient synaptic vesicle recycling is promoted. 7,9,34 Retino-cortical visual processing defects and body and wing size reduction are seen in both Dyrk1a ( ± ) and the mnb fly. 35,36 Dyrk1a-haploinsufficient mice show severe glucose intolerance and decreased beta cell proliferation.…”

“…5,6 Furthermore, data from both animal models and humans have suggested that decreased DYRK1A expression is also pathogenic. [7][8][9] Pathogenic variants in DYRK1A resulting in haploinsufficiency of the gene have recently been proposed to cause intellectual disability (ID), mental retardation autosomal dominant type 7 (MIM 614104) in individuals with translocations, 10 single-nucleotide variants (SNVs), 11,12 and intragenic microdeletions 11,[13][14][15][16][17] disrupting only DYRK1A.…”

Increased Dosage of DYRK1A and Brain Volumetric Alterations in a YAC Model of Partial Trisomy 21

“…The DYRK1A gene, which is carried on YAC152F7 but not on YAC141G6, encodes a serine threonine kinase. A study of mice with only one active copy of DYRK1A (heterozygous for DYRK1A invalidation) showed that a decrease in DYRK1A expression decreases the size of the ventral regions of the brain, including the thalamus-hypothalamus area (Fotaki et al, 2002). This finding suggests that, in YAC152F7 transgenic mice, which carry three copies of DYRK1A, DYRK1A overexpression is responsible for phenotypic changes opposite to those observed in heterozygous mice with one copy of DYRK1A.…”

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

“…DYRK1A has been considered a good candidate gene for the Down syndrome phenotypic abnormalities (reviewed in Epstein, 2000;Vicari et al, 2000;Nadel, 2003) due to its localization in the Down syndrome critical region of chromosome 21 (Rahmani et al, 1989(Rahmani et al, , 1990Delabar et al, 1993;Shindoh et al, 1996;Song et al, 1996), its overexpression in the brain of Down syndrome patients (Guimera et al, 1999), and the neurobehavioral alterations shown by transgenic mice overexpressing the gene (Smith and Rubin, 1997;Altafaj et al, 2001). The recent observation that the size of dendrites in some brain areas is reduced in DYRK1A haploinsufficient mice indicates that DYRK1A dose reduction could affect the length and the complexity of the dendrites (Fotaki et al, 2002). Moreover, brains of patients with Down syndrome present size reduction, increased astrocyte number, delayed myelination, and several abnormal neuronal differentiation processes (reviewed in Coyle et al, 1986;Becker et al, 1991;Raz et al, 1995).…”