Notch targets the Cdk inhibitor Xic1 to regulate differentiation but not the cell cycle in neurons.
The proneural protein neurogenin (XNGNR1) drives differentiation of primary neurons in combination with the cyclin-dependent kinase (Cdk) inhibitor Xic1. Differentiation is inhibited by Notch signalling, resulting in a scattered neuronal distribution. Here we show that Notch signalling regulates the level of Xic1 transcription, yet this does not correlate with Notch's ability to perturb the cell cycle. Instead, Notch may regulate Xic1 levels to control its differentiation function directly, which is required in parallel with XNGNR1 to promote primary neurogenesis. Indeed, Notch-mediated repression of both XNGNR1 and Xic1 must be relieved for neuronal differentiation to occur. Interestingly, although Xic1 is required for XNGNR1-mediated neurogenesis, it is not required for XNGNR1-mediated upregulation of Delta, allowing establishment of the negative feedback loop involved in lateral inhibition. Therefore, Notch targets Cdk inhibitor expression to regulate differentiation of primary neurons, and its effects on the cell cycle may be of secondary importance.
Vernon
Ann E
AE
Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XZ, UK.
Movassagh
Mehregan
M
Horan
Ian
I
Wise
Helen
H
Ohnuma
Shinichi
S
Philpott
Anna
A
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology; D001616:beta-Galactosidase / Q000378:metabolism
D051880:Receptors, Notch; D029867:Xenopus Proteins; C493963:Xicl protein, Xenopus; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001616:beta-Galactosidase