DYRK1A: A master regulatory protein controlling brain growth

abstract Article history:Received 8 October 2011Revised 18 December 2011Accepted 14 January 2012Available online 26 January 2012 Copy number variation in a small region of chromosome 21 containing DYRK1A produces morphological andcognitive alterations in human. In mouse models, haploinsufficiency results in microcephaly, and a humanDYRK1A gain-of-function model (three alleles) exhibits increasedbrain volume. To investigate these develop-mental aspects, we used a murine BAC clone containing the entire gene to construct anoverexpression modeldriven by endogenous regulatory sequences. We compared this new model to two other mouse models withthree 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, wereobserved in both the BAC transgenic and Ts65Dn mice. Using unbiased stereology we found that, in thecortex, neuron density is inversely related to Dyrk1a copy number but, in thalamic nuclei, neuron densityis 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 duringbrain 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.