DRE-1/FBXO11-dependent degradation of BLMP-1/BLIMP-1 governs C. elegans developmental timing and maturation.

Developmental timing genes catalyze stem cell progression and animal maturation programs across taxa. Caenorhabditis elegans DRE-1/FBXO11 functions in an SCF E3-ubiquitin ligase complex to regulate the transition to adult programs, but its cognate proteolytic substrates are unknown. Here, we identify the conserved transcription factor BLMP-1 as a substrate of the SCF(DRE-1/FBXO11) complex. blmp-1 deletion suppressed dre-1 mutant phenotypes and exhibited developmental timing defects opposite to dre-1. blmp-1 also opposed dre-1 for other life history traits, including entry into the dauer diapause and longevity. BLMP-1 protein was strikingly elevated upon dre-1 depletion and dysregulated in a stage- and tissue-specific manner. The role of DRE-1 in regulating BLMP-1 stability is evolutionary conserved, as we observed direct protein interaction and degradation function for worm and human counterparts. Taken together, posttranslational regulation of BLMP-1/BLIMP-1 by DRE-1/FBXO11 coordinates C. elegans developmental timing and other life history traits, suggesting that this two-protein module mediates metazoan maturation processes.

[1]  Steve D. M. Brown,et al.  Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: the Minnesota COME/ROM Family Study. , 2006, Archives of otolaryngology--head & neck surgery.

[2]  A. Rougvie,et al.  miRNAs give worms the time of their lives: Small RNAs and temporal control in Caenorhabditis elegans , 2010, Developmental dynamics : an official publication of the American Association of Anatomists.

[3]  T. Suda,et al.  A Germ Cell-specific Gene, Prmt5, Works in Somatic Cell Reprogramming , 2011, The Journal of Biological Chemistry.

[4]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[5]  Govind Bhagat,et al.  BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. , 2010, Cancer cell.

[6]  H. Horvitz,et al.  The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. , 2005, Developmental cell.

[7]  Steve D. M. Brown,et al.  The Deaf Mouse Mutant Jeff (Jf) is a Single Gene Model of Otitis Media , 2003, Journal of the Association for Research in Otolaryngology.

[8]  M. Nussenzweig,et al.  Blimp1 Defines a Progenitor Population that Governs Cellular Input to the Sebaceous Gland , 2006, Cell.

[9]  Steve D. M. Brown,et al.  A mutation in the F-box gene, Fbxo11, causes otitis media in the Jeff mouse. , 2006, Human molecular genetics.

[10]  K. Skorija,et al.  Vitamin D receptor is essential for normal keratinocyte stem cell function , 2007, Proceedings of the National Academy of Sciences.

[11]  Iva Greenwald,et al.  OrthoList: A Compendium of C. elegans Genes with Human Orthologs , 2011, PloS one.

[12]  S. Brenner.  The genetics of Caenorhabditis elegans. , 1974, Genetics.

[13]  F. Slack,et al.  The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. , 2000, Molecular cell.

[14]  R. Kamath,et al.  Genome-wide RNAi screening in Caenorhabditis elegans. , 2003, Methods.

[15]  Ryan M. O’Connell,et al.  Physiological and pathological roles for microRNAs in the immune system , 2010, Nature Reviews Immunology.

[16]  K. Calame,et al.  Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1 , 2007, Proceedings of the National Academy of Sciences.

[17]  Mark M. Davis,et al.  The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse , 2005, Development.

[18]  Mark M. Davis,et al.  Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells , 1994, Cell.

[19]  Eduard Batlle,et al.  The circadian molecular clock creates epidermal stem cell heterogeneity , 2011, Nature.

[20]  A. Rougvie,et al.  Novel heterochronic functions of the Caenorhabditis elegans period-related protein LIN-42. , 2006, Developmental biology.

[21]  C. Tunyaplin,et al.  Characterization of the B lymphocyte-induced maturation protein-1 (Blimp-1) gene, mRNA isoforms and basal promoter. , 2000, Nucleic acids research.

[22]  K. Calame,et al.  Regulation and functions of Blimp-1 in T and B lymphocytes. , 2008, Annual review of immunology.

[23]  F. Slack,et al.  The nuclear receptor gene nhr-25 plays multiple roles in the Caenorhabditis elegans heterochronic gene network to control the larva-to-adult transition. , 2010, Developmental biology.

[24]  A. Rougvie,et al.  The Caenorhabditis elegans hunchback-like gene lin-57/hbl-1 controls developmental time and is regulated by microRNAs. , 2003, Developmental cell.

[25]  S. Crotty,et al.  Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation , 2010, Nature Immunology.

[26]  Michele Pagano,et al.  FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas , 2012, Nature.

[27]  L. Staudt,et al.  Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma , 2013, Proceedings of the National Academy of Sciences.

[28]  A. Rougvie,et al.  The heterochronic gene lin-29 encodes a zinc finger protein that controls a terminal differentiation event in Caenorhabditis elegans. , 1995, Development.

[29]  Kerstin Neubert,et al.  DRE-1: an evolutionarily conserved F box protein that regulates C. elegans developmental age. , 2007, Developmental cell.

[30]  Jong-Won Kim,et al.  LIN28B polymorphisms are associated with central precocious puberty and early puberty in girls , 2012, Korean journal of pediatrics.

[31]  H. Horvitz,et al.  MAB-10/NAB acts with LIN-29/EGR to regulate terminal differentiation and the transition from larva to adult in C. elegans , 2011, Development.

[32]  L. Smirnova,et al.  The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2 , 2009, Nature Cell Biology.

[33]  J. Sulston,et al.  Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. , 1977, Developmental biology.

[34]  M. Azim Surani,et al.  Blimp1 is a critical determinant of the germ cell lineage in mice , 2005, Nature.

[35]  Michele Pagano,et al.  Mechanisms and function of substrate recruitment by F-box proteins , 2013, Nature Reviews Molecular Cell Biology.

[36]  H. Ohta,et al.  A Signaling Principle for the Specification of the Germ Cell Lineage in Mice , 2009, Cell.

[37]  Matko Bosnjak,et al.  REVIGO Summarizes and Visualizes Long Lists of Gene Ontology Terms , 2011, PloS one.

[38]  Zuoyan Zhu,et al.  The Caenorhabditis elegans PcG-like Gene sop-2 Regulates the Temporal and Sexual Specificities of Cell Fates , 2008, Genetics.

[39]  R. Dalla‐Favera,et al.  Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells , 2007, Nature Immunology.

[40]  M. Pagano,et al.  Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. , 2013, Molecular cell.

[41]  Gary Ruvkun,et al.  Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. , 2007, Genes & development.

[42]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[43]  S. Muljo,et al.  Lin28b Reprograms Adult Bone Marrow Hematopoietic Progenitors to Mediate Fetal-Like Lymphopoiesis , 2012, Science.

[44]  H. Horvitz,et al.  Heterochronic mutants of the nematode Caenorhabditis elegans. , 1984, Science.

[45]  M. Jindra,et al.  Nuclear receptor NHR-25 is required for cell-shape dynamics during epidermal differentiation in Caenorhabditis elegans , 2005, Journal of Cell Science.

[46]  Anindya Dutta,et al.  CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. , 2013, Molecular cell.

[47]  E. Fuchs,et al.  Specific microRNAs are preferentially expressed by skin stem cells to balance self-renewal and early lineage commitment. , 2011, Cell stem cell.

[48]  A. Sluder,et al.  nhr-25, the Caenorhabditis elegans ortholog of ftz-f1, is required for epidermal and somatic gonad development. , 2000, Developmental biology.

[49]  M. Nelson,et al.  A Bow-Tie Genetic Architecture for Morphogenesis Suggested by a Genome-Wide RNAi Screen in Caenorhabditis elegans , 2011, PLoS genetics.