DYRK1A: A master regulatory protein controlling brain growth
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-04-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112000228 |
| _version_ | 1818350593261961216 |
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| author | Fayçal Guedj Patricia Lopes Pereira Sonia Najas Maria-Jose Barallobre Caroline Chabert Benoit Souchet Catherine Sebrie Catherine Verney Yann Herault Mariona Arbones Jean M. Delabar |
| author_facet | Fayçal Guedj Patricia Lopes Pereira Sonia Najas Maria-Jose Barallobre Caroline Chabert Benoit Souchet Catherine Sebrie Catherine Verney Yann Herault Mariona Arbones Jean M. Delabar |
| author_sort | Fayçal Guedj |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T18:24:18Z |
| format | Article |
| id | doaj.art-db3d5b2c8d124690bf6c0cdc300b6366 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:24:18Z |
| publishDate | 2012-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-db3d5b2c8d124690bf6c0cdc300b63662022-12-21T23:35:38ZengElsevierNeurobiology of Disease1095-953X2012-04-01461190203DYRK1A: A master regulatory protein controlling brain growthFayçal Guedj0Patricia Lopes Pereira1Sonia Najas2Maria-Jose Barallobre3Caroline Chabert4Benoit Souchet5Catherine Sebrie6Catherine Verney7Yann Herault8Mariona Arbones9Jean M. Delabar10Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC CNRS 4413, 75205 Paris, FranceInstitut 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, FranceInstituto de Biología Molecular de Barcelona (CSIC), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Barcelona, SpainInstituto de Biología Molecular de Barcelona (CSIC), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Barcelona, SpainUniv Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC CNRS 4413, 75205 Paris, FranceUniv Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC CNRS 4413, 75205 Paris, FranceLaboratoire de RMN Biologique, ICSN-CNRS, Gif sur Yvette, FranceUniv Paris Diderot, Sorbonne Paris Cité, Inserm U676, PremUP, 75205, Paris, FranceInstitut 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; Transgenese et Archivage Animaux Modèles, TAAM, CNRS, UPS44, 3B rue de la Férollerie 45071 Orléans, FranceInstituto de Biología Molecular de Barcelona (CSIC), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Barcelona, SpainUniv Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC CNRS 4413, 75205 Paris, France; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S0969996112000228 |
| spellingShingle | Fayçal Guedj Patricia Lopes Pereira Sonia Najas Maria-Jose Barallobre Caroline Chabert Benoit Souchet Catherine Sebrie Catherine Verney Yann Herault Mariona Arbones Jean M. Delabar DYRK1A: A master regulatory protein controlling brain growth Neurobiology of Disease |
| title | DYRK1A: A master regulatory protein controlling brain growth |
| title_full | DYRK1A: A master regulatory protein controlling brain growth |
| title_fullStr | DYRK1A: A master regulatory protein controlling brain growth |
| title_full_unstemmed | DYRK1A: A master regulatory protein controlling brain growth |
| title_short | DYRK1A: A master regulatory protein controlling brain growth |
| title_sort | dyrk1a a master regulatory protein controlling brain growth |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112000228 |
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