title: Modulation of p53 and met expression by Krüppel-like factor 8 regulates zebrafish cerebellar development.
abstract: Krüppel-like factor 8 (Klf8) is a zinc-finger transcription factor implicated in cell proliferation, and cancer cell survival and invasion; however, little is known about its role in normal embryonic development. Here, we show that Klf8 is required for normal cerebellar development in zebrafish embryos. Morpholino knockdown of klf8 resulted in abnormal cerebellar primordium morphology and the induction of p53 in the brain region at 24 hours post-fertilization (hpf). Both p53-dependent reduction of cell proliferation and augmentation of apoptosis were observed in the cerebellar anlage of 24 hpf-klf8 morphants. In klf8 morphants, expression of ptf1a in the ventricular zone was decreased from 48 to 72 hpf; on the other hand, expression of atohla in the upper rhombic lip was unaffected. Consistent with this finding, Purkinje cell development was perturbed and granule cell number was reduced in 72 hpf-klf8 morphants; co-injection of p53 MO(sp) or klf8 mRNA substantially rescued development of cerebellar Purkinje cells in klf8 morphants. Hepatocyte growth factor/Met signaling is known to regulate cerebellar development in zebrafish and mouse. We observed decreased met expression in the tectum and rhombomere 1 of 24 hpf-klf8 morphants, which was largely rescued by co-injection with klf8 mRNA. Moreover, co-injection of met mRNA substantially rescued formation of Purkinje cells in klf8 morphants at 72 hpf. Together, these results demonstrate that Klf8 modulates expression of p53 and met to maintain ptf1a-expressing neuronal progenitors, which are required for the appropriate development of cerebellar Purkinje and granule cells in zebrafish embryos.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Neihu, Taipei, Taiwan, 114, Republic of China.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Tsai
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taipei, Taiwan, 115, Republic of China.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Lu
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taipei, Taiwan, 115, Republic of China.|Institute of Zoology, National Taiwan University, Taipei, Taiwan, 10617, Republic of China.
authors.forename: Yu-Hsiu
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan, 115, Republic of China.
authors.forename: Huang-Wei
authors.initials: HW
authors.lastname: Lien
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Neihu, Taipei, Taiwan, 114, Republic of China.|Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan, 115, Republic of China.
authors.forename: Chang-Jen
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taipei, Taiwan, 115, Republic of China.
authors.forename: Jen-Leih
authors.initials: JL
authors.lastname: Wu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Neihu, Taipei, Taiwan, 114, Republic of China.|Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taipei, Taiwan, 115, Republic of China.
authors.forename: Sheng-Ping L
authors.initials: SP
authors.lastname: Hwang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology; D002531:Cerebellum / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D060172:Morpholinos; D009154:Mutation; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D003336:Tectum Mesencephali / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C514187:Atoh1a protein, zebrafish; C000607569:KLF8 protein, zebrafish; D051741:Kruppel-Like Transcription Factors; D060172:Morpholinos; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C571228:tp53 protein, zebrafish; C062602:transcription factor PTF1; D019859:Proto-Oncogene Proteins c-met
keywords: Klf8; apoptosis; cerebellum; met; p53; zebrafish