title: CDKL5, a novel MYCN-repressed gene, blocks cell cycle and promotes differentiation of neuronal cells.
abstract: Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene are associated with a severe epileptic encephalopathy (early infantile epileptic encephalopathy type 2, EIEE2) characterized by early-onset intractable seizures, infantile spasms, severe developmental delay, intellectual disability, and Rett syndrome (RTT)-like features. Despite the clear involvement of CDKL5 mutations in intellectual disability, the function of this protein during brain development and the molecular mechanisms involved in its regulation are still unknown. Using human neuroblastoma cells as a model system we found that an increase in CDKL5 expression caused an arrest of the cell cycle in the G(0)/G(1) phases and induced cellular differentiation. Interestingly, CDKL5 expression was inhibited by MYCN, a transcription factor that promotes cell proliferation during brain development and plays a relevant role in neuroblastoma biology. Through a combination of different and complementary molecular and cellular approaches we could show that MYCN acts as a direct repressor of the CDKL5 promoter. Overall our findings unveil a functional axis between MYCN and CDKL5 governing both neuron proliferation rate and differentiation. The fact that CDKL5 is involved in the control of both neuron proliferation and differentiation may help understand the early appearance of neurological symptoms in patients with mutations in CDKL5.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valli
authors.forename: Stefania
authors.initials: S
authors.lastname: Trazzi
authors.forename: Claudia
authors.initials: C
authors.lastname: Fuchs
authors.forename: Daniela
authors.initials: D
authors.lastname: Erriquez
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
mesh_terms: D000818:Animals; D001921:Brain; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D000073376:Epileptic Syndromes; D006801:Humans; D051379:Mice; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013036:Spasms, Infantile / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C459801:MYCN protein, human; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human; C533690:CDKL5 protein, mouse