The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development.
The precise regulation of programmed cell death is critical for the normal development of the nervous system. We show here that DYRK1A (minibrain), a protein kinase essential for normal growth, is a negative regulator of the intrinsic apoptotic pathway in the developing retina. We provide evidence that changes in Dyrk1A gene dosage in the mouse strongly alter the cellularity of inner retina layers and result in severe functional alterations. We show that DYRK1A does not affect the proliferation or specification of retina progenitor cells, but rather regulates the number of cells that die by apoptosis. We demonstrate that DYRK1A phosphorylates caspase-9 on threonine residue 125, and that this phosphorylation event is crucial to protect retina cells from apoptotic cell death. Our data suggest a model in which dysregulation of the apoptotic response in differentiating neurons participates in the neuropathology of diseases that display DYRK1A gene-dosage imbalance effects, such as Down's syndrome.
Laguna
Ariadna
A
Center for Genomic Regulation, UPF, 08003 Barcelona, Spain.
Aranda
Sergi
S
Barallobre
María José
MJ
Barhoum
Rima
R
Fernández
Eduardo
E
Fotaki
Vassiliki
V
Delabar
Jean Maurice
JM
de la Luna
Susana
S
de la Villa
Pedro
P
Arbonés
Maria L
ML
D000818:Animals; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism*; D049109:Cell Proliferation; D004596:Electroretinography / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000196:embryology* / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry; D000097603:Dyrk Kinases
D053453:Caspase 9; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D013912:Threonine; D000097603:Dyrk Kinases