title: DYRK1A: a master regulatory protein controlling brain growth.
abstract: 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 developmental 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 controlling the structure of neuronal components.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC CNRS 4413, 75205 Paris, France.
authors.forename: Fayçal
authors.initials: F
authors.lastname: Guedj
authors.forename: Patricia Lopes
authors.initials: PL
authors.lastname: Pereira
authors.forename: Sonia
authors.initials: S
authors.lastname: Najas
authors.forename: Maria-Jose
authors.initials: MJ
authors.lastname: Barallobre
authors.forename: Caroline
authors.initials: C
authors.lastname: Chabert
authors.forename: Benoit
authors.initials: B
authors.lastname: Souchet
authors.forename: Catherine
authors.initials: C
authors.lastname: Sebrie
authors.forename: Catherine
authors.initials: C
authors.lastname: Verney
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.forename: Mariona
authors.initials: M
authors.lastname: Arbones
authors.forename: Jean M
authors.initials: JM
authors.lastname: Delabar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000502:physiology*; D049109:Cell Proliferation; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases