Zebrafish usp39 mutation leads to rb1 mRNA splicing defect and pituitary lineage expansion.
Loss of retinoblastoma (Rb) tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish ubiquitin specific peptidase 39 (usp39) mutation, the yeast and human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion without apparent changes in major hypothalamic hormonal and regulatory signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression. Rb1 mRNA overexpression, or antisense morpholino knockdown of e2f4, partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon. These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis.
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.
Yesenia
Y
Ríos
Shlomo
S
Melmed
Shuo
S
Lin
Ning-Ai
NA
Liu
D000818:Animals; D019070:Cell Lineage; D010450:Endopeptidases / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D009154:Mutation; D010902:Pituitary Gland / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics*
D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D029961:Zebrafish Proteins; D010450:Endopeptidases; C556673:Usp39 protein, zebrafish
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