Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration.
Down syndrome is the most frequent genetic cause of mental retardation, having an incidence of 1 in 700 live births. In the present study we used a transgenic mouse in vivo library consisting of 4 yeast artificial chromosome (YAC) transgenic mouse lines, each bearing a different fragment of the Down syndrome critical region 1 (DCR-1), implicated in brain abnormalities characterizing this pathology. The 152F7 fragment, in addition to genes also located on the other DCR-1 fragments, bears the DYRK1A gene, encoding for a serine-threonine kinase. The neurobehavioral analysis of these mouse lines showed that DYRK1A overexpressing 152F7 mice but not the other lines display learning impairment and hyperactivity during development. Additionally, 152F7 mice display increased brain weight and neuronal size. At a biochemical level we found DYRK1A overexpression associated with a development-dependent increase in phosphorylation of the transcription factor FKHR and with high levels of cyclin B1, suggesting for the first time in vivo a correlation between DYRK1A overexpression and cell cycle protein alteration. In addition, we found an altered phosphorylation of transcription factors of CREB family. Our findings support a role of DYRK1A overexpression in the neuronal abnormalities seen in Down syndrome and suggest that this pathology is linked to altered levels of proteins involved in the regulation of cell cycle.
Branchi
Igor
I
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy. branchi@iss.it
Bichler
Zoë
Z
Minghetti
Luisa
L
Delabar
Jean Maurice
JM
Malchiodi-Albedi
Fiorella
F
Gonzalez
Marie-Claude
MC
Chettouh
Zoubidda
Z
Nicolini
Alessia
A
Chabert
Caroline
C
Smith
Desmond J
DJ
Rubin
Edward M
EM
Migliore-Samour
Danièle
D
Alleva
Enrico
E
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D048429:Cell Size / Q000235:genetics; D002869:Chromosome Aberrations; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015698:Genomic Library; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D007859:Learning Disabilities / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009929:Organ Size / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D000097603:Dyrk Kinases
D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D019926:Cyclin B; D056744:Cyclin B1; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D014157:Transcription Factors; D000097603:Dyrk Kinases; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; C486303:Dscr1l1 protein, mouse; C085126:FOXO1 protein, human; C467200:Foxo1 protein, mouse; C100360:RCAN2 protein, human