DYRK1A: A master regulatory protein controlling brain growth Fayçal Guedj a , Patricia Lopes Pereira b , Sonia Najas c, d , Maria-Jose Barallobre c, d , Caroline Chabert a , Benoit Souchet a , Catherine Sebrie e , Catherine Verney f , Yann Herault b, g , Mariona Arbones c, d , Jean M. Delabar a, ⁎ a Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC CNRS 4413, 75205 Paris, France b Institut de Génétique Biologie Moléculaire et Cellulaire, Translational Medicine and Neuroscience Program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964, Institut Clinique de la Souris, ICS, 1 rue Laurent Fries, 67404 Illkirch, France c Instituto de Biología Molecular de Barcelona (CSIC), Barcelona, Spain d Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Barcelona, Spain e Laboratoire de RMN Biologique, ICSN-CNRS, Gif sur Yvette, France f Univ Paris Diderot, Sorbonne Paris Cité, Inserm U676, PremUP, 75205, Paris, France g Transgenese et Archivage Animaux Modèles, TAAM, CNRS, UPS44, 3B rue de la Férollerie 45071 Orléans, France abstract article info Article history: Received 8 October 2011 Revised 18 December 2011 Accepted 14 January 2012 Available online 26 January 2012 Copy number variation in a small region of chromosome 21 containing DYRK1A produces morphological and cognitive alterations in human. In mouse models, haploinsufficiency results in microcephaly, and a human DYRK1A gain-of-function model (three alleles) exhibits increased brain volume. To investigate these develop- mental aspects, we used a murine BAC clone containing the entire gene to construct an overexpression model driven by endogenous regulatory sequences. We compared this new model to two other mouse models with three copies of Dyrk1a, YACtgDyrk1a and Ts65Dn, as well as the loss-of-function model with one copy (Dyrk1a +/- ). Growth, viability, brain weight, and brain volume depended strongly upon gene copy number. Brain region-specific variations observed in gain-of-function models mirror their counterparts in the loss-of- function model. Some variations, such as increased volume of the superior colliculus and ventricles, were observed in both the BAC transgenic and Ts65Dn mice. Using unbiased stereology we found that, in the cortex, neuron density is inversely related to Dyrk1a copy number but, in thalamic nuclei, neuron density is directly related to copy number. In addition, six genes involved either in cell division (Ccnd1 and pAkt) or in neuronal machinery (Gap43, Map2, Syp, Snap25) were regulated by Dyrk1a throughout development, from birth to adult. These results imply that Dyrk1a expression alters different cellular processes during brain development. Dyrk1a, then, has two roles in the development process: shaping the brain and control- ling the structure of neuronal components. © 2012 Elsevier Inc. All rights reserved. Introduction Down syndrome, DS, generally resulting from trisomy 21 (T21), occurs in 1 in 700 live births and accounts for close to 40% of cases of moderate to severe mental retardation in the general population. Nervous system involvement, which affects patients throughout their lifespan, results in deficits involving learning, memory, lan- guage, and movement. Mental retardation—to varying extents—is essentially universal in DS. Structural alterations with hypoplasia of the brain and cerebellum (Pinter et al., 2001), ultrastructural modifications with lamination delays (Golden and Hyman, 1994) and dendritic anomalies (Kaufmann and Moser, 2000) arise during development and modify various brain regions, including the cerebral cortex and hippocampus. In addition, characteristic cognitive deficits have been described (Brown et al., 2003; Pennington et al., 2003). By adulthood, the DS brain is clearly microcephalic, but differen- tially greater volume reductions occur in the hippocampus, prefrontal cortex, and cerebellum. Several features of the adult brain phenotype begin to emerge in the first months of life. These include microceph- aly and reduced volumes of the cerebellum and frontal lobes, and data collected on brain weight of fetuses indicate a significant de- crease, by 12–13%, in brain weight/body weight ratio as early as 15–18 weeks into gestation (Guihard-Costa et al., 2006). This mor- phogenetic alteration is not homogeneous throughout the brain; in particular, infratentorial brain weight/total brain weight ratio appears to be higher in the brains of fetuses with T21. Regional magnetic resonance (MR) imaging has shown similar differences in the brains of children with T21, with an increase in relative volumes of two Neurobiology of Disease 46 (2012) 190–203 ⁎ Corresponding author. E-mail address: delabar@univ-paris-diderot.fr (J.M. Delabar). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2012.01.007 Contents lists available at SciVerse ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi