cables1 is required for embryonic neural development: molecular, cellular, and behavioral evidence from the zebrafish.
In vitro studies have suggested that the Cables1 gene regulates epithelial cell proliferation, whereas other studies suggest a role in promoting neural differentiation. In efforts to clarify the functions of Cables1 in vivo, we conducted gain- and loss-of-function studies targeting its ortholog (cables1) in the zebrafish embryo. Similar to rodents, zebrafish cables1 mRNA expression is detected most robustly in embryonic neural tissues. Antisense knockdown of cables1 leads to increased numbers of apoptotic cells, particularly in brain tissue, in addition to a distinct behavioral phenotype, characterized by hyperactivity in response to stimulation. Apoptosis and the behavioral abnormality could be rescued by co-expression of a morpholino-resistant cables1 construct. Suppression of p53 expression in cables1 morphants partially rescued both apoptosis and the behavioral phenotype, suggesting that the phenotype of cables1 morphants is due in part to p53-dependent apoptosis. Alterations in the expression patterns of several neural transcription factors were observed in cables1 morphants during early neurulation, suggesting that cables1 is required for early neural differentiation. Ectopic overexpression of cables1 strongly disrupted embryonic morphogenesis, while overexpression of a cables1 mutant lacking the C-terminal cyclin box had little effect, suggesting functional importance of the cyclin box. Lastly, marked reductions in p35, but not Cdk5, were observed in cables1 morphants. Collectively, these data suggest that cables1 is important for neural differentiation during embryogenesis, in a mechanism that likely involves interactions with the Cdk5/p35 kinase pathway.
Vincent Center for Reproductive Biology, MGH Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Jolijn W
JW
Groeneweg
Yvonne A R
YA
White
David
D
Kokel
Randall T
RT
Peterson
Lawrence R
LR
Zukerberg
Inna
I
Berin
Bo R
BR
Rueda
Antony W
AW
Wood
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D009420:Nervous System / Q000166:cytology / Q000196:embryology*; D055495:Neurogenesis / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics
D002352:Carrier Proteins; D016213:Cyclins; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C557751:cables1 protein, zebrafish; D051360:Cyclin-Dependent Kinase 5
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