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CRAZY ABOUT BIOMECIDINE Having a look into frog oocytes

CRAZY ABOUT BIOMECIDINE Having a look into frog oocytes. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS. Gene expression Gene regulation Translational control of mRNAs

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CRAZY ABOUT BIOMECIDINE Having a look into frog oocytes

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  1. CRAZY ABOUT BIOMECIDINE Having a look into frog oocytes TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS

  2. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS • Gene expression • Gene regulation • Translational control of mRNAs • CPEBs & cytoplasmic polyadenylation • Meiosis and translational control of mRNAs mediated by CPEBs • CPEBs beyond meiosis…

  3. GENE EXPRESSION Cell signaling Cell adhesion Enzymes Define the structure Transport … Genetic information Effectors

  4. GENE EXPRESSION Cell signaling Cell adhesion Enzymes Define the structure Transport … Genetic information Effectors Key steps in gene expression • RNA transcription: from DNA to RNA • RNA processing: from RNA to mRNA • mRNA transport: from the nucleus to the cytoplasm • Protein translation: from mRNA to protein

  5. GENE EXPRESSION Cell signaling Cell adhesion Enzymes Define the structure Transport … Genetic information Effectors RNA processing DNA Pre-mRNA mRNA

  6. GENE EXPRESSION Cell signaling Cell adhesion Enzymes Define the structure Transport … Genetic information Effectors mRNA features UGA AUG 5’ cap CDS AAAAAAAAAA 5’UTR 3’UTR

  7. GENE EXPRESSION Cell signaling Cell adhesion Enzymes Define the structure Transport … Genetic information Effectors Protein translation

  8. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS • Gene expression • Gene regulation • Translational control of mRNAs • CPEBs & cytoplasmic polyadenylation • Meiosis and translational control of mRNAs mediated by CPEBs • CPEBs beyond meiosis…

  9. GENE REGULATION EVERY CELL IN A GIVEN ORGANISM CONTAINS THE SAME GENETIC INFORMATION DIFFERENCES IN GENE EXPRESSION

  10. GENE REGULATION • Every step in gene expression is regulated TRANSCRIPTION Accessibility of DNA Transcriptional regulation

  11. GENE REGULATION • Every step in gene expression is regulated AUG 5’ cap TRANSCRIPTION CDS AAA 5’UTR 3’UTR Accessibility of DNA Transcriptional regulation AUG CDS AAA RNA PROCESSING Alternative splicing Alternative 3’UTR formation: different 3’UTR

  12. GENE REGULATION • Every step in gene expression is regulated TRANSCRIPTION Accessibility of DNA Transcriptional regulation RNA PROCESSING Alternative splicing Alternative 3’UTR formation: different 3’UTR PROTEIN TRANSLATION Global vs. mRNA specific regulation Translational repression precluding ribosome recruitment or progression through the mRNA

  13. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS • Gene expression • Gene regulation • Translational control of mRNAs • CPEBs & cytoplasmic polyadenylation • Meiosis and translational control of mRNAs mediated by CPEBs • CPEBs beyond meiosis…

  14. TRANSLATIONAL CONTROL OF mRNAs WHY mRNAs should be stored in the cytoplasm instead of being immediately translated? Once transcribed, mRNAs can have different fates…. cytoplasm nucleus AAAAAA A AAAAAA AAAAAA AAAAAA

  15. TRANSLATIONAL CONTROL OF mRNAs WHY mRNAs should be stored in the cytoplasm instead of being immediately translated? Absolutely required in situations with absence of transcription To solve long distances (axons can extend up to 1 meter!) Rapid response

  16. TRANSLATIONAL CONTROL OF mRNAs • mRNA translation can be divided into 3 phases: initiation, elongation and termination • INITIATION is the phase more tightly controlled All mRNAs exit the nucleus with a long poly(A) tail and should be efficiently translated…

  17. TRANSLATIONAL CONTROL OF mRNAs sequestering initiation factors blocking the 5’ cap shortening the poly(A) tail HOW TO CONTROL TRANSLATION AT INITITATION? AAAAAAAAAAAAA 4G 4E Sequester initiation factors 4E 4E-BP

  18. TRANSLATIONAL CONTROL OF mRNAs sequestering initiation factors blocking the 5’ cap shortening the poly(A) tail HOW TO CONTROL TRANSLATION AT INITITATION? AAAAAAAAAAAAA 4G 4E Block the 5’ cap  no recruitment of the ribosome AAAAAAAAAAAAA 4E

  19. TRANSLATIONAL CONTROL OF mRNAs sequestering initiation factors blocking the 5’ cap shortening the poly(A) tail HOW TO CONTROL TRANSLATION AT INITITATION? AAAAAAAAAAAAA 4G 4E Shorten the poly(A) tail  no close loop A 4E

  20. TRANSLATIONAL CONTROL OF mRNAs sequestering initiation factors blocking the 5’ cap shortening the poly(A) tail HOW TO CONTROL TRANSLATION AT INITITATION? TRANSLATIONAL REPRESSION doesn’t last forever!!! AAAAAAAAAAAAA How to activate translation? 4G releasing initiation factors allowing the 5’ cap to interact with initiation factors elongating the poly(A) tail 4E Cell stimuli Activation of mRNA translation

  21. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS • Gene expression • Gene regulation • Translational control of mRNAs • CPEBs & cytoplasmic polyadenylation • Meiosis and translational control of mRNAs mediated by CPEBs • CPEBs beyond meiosis…

  22. CPEBs and CYTOPLASMIC POLYADENYLATION NO TRANSLATION AAAAAAAAAAAAA 4G 4E A TRANSLATION 4E Polyadenylation can happen in the cytoplasm!!!!

  23. CPEBs and CYTOPLASMIC POLYADENYLATION CPEBs play an essential role RNA binding proteins Bind to specific sequences in the 3’UTR of target mRNAs Have a dual function!!!! WHAT MAKES THE DIFFERENCE???? stimulus Kinase activation CPEB in repression CPEB in activation CPEB recruits other proteins that shorten the poly(A) tail and block the cap CPEB recruits other proteins that elongate the poly(A) tail

  24. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS • Gene expression • Gene regulation • Translational control of mRNAs • CPEBs & cytoplasmic polyadenylation • Meiosis and translational control of mRNAs mediated by CPEBs • CPEBs beyond meiosis…

  25. MEIOSIS and CPEBs

  26. MEIOSIS and CPEBs • Model system: Xenopus laevis oocytes • Oocytes arrested at the prophase of meiosis I (progesterone makes them progress to metaphase of meiosis II) • Eggs arrested at the metaphase of meiosis II (fertilization makes them finish meiosis and start embryonic divisions) Eggs Oocytes progesterone fertilization

  27. MEIOSIS and CPEBs • Model system: Xenopus laevis oocytes • Prophase I arrested oocytes grow until they are fully competent for development: 6 growth stages MEIOSIS AND FIRST EMBRYIONIC DIVISIONS HAPPEN IN THE ABSENCE OF TRANSCRIPTION! >1.2mm! (human: 0.12mm) Accumulation of molecular reserves… Like maternal mRNAs! PROTEIN EXPRESSION DUE TO TRANSLATIONAL ACTIVATION OF mRNAs!

  28. MEIOSIS and CPEBs • Model system: Xenopus laevis oocytes • Meiotic progression requires protein translation!!!! Requires activation of translation of stored mRNAs sVI. Oocytes progesterone

  29. MEIOSIS and CPEBs • Model system: Xenopus laevis oocytes • Meiotic progression requires protein translation!!!! MEIOSIS RESUMPTION + progesterone CPEB1 is phosphorylated Activation of translation of mRNAs Stage VI oocytes store A LOT of maternal mRNAs repressed by CPEB1

  30. MEIOSIS and CPEBs • CPEB1 is not the only one! CPEB4 takes the job in late meiotic phases. CPEB1 CPEB4 CPEB1 degraded CPEB4 synthetized repression activation prog. Oocytes arrested

  31. CURIOSITY… THE POWER OF THE CYTOPLASM! Early development happens in the absence of transcription Everything you need for early development is contained in the egg cytoplasm

  32. TRANSLATIONAL CONTROL OF mRNAs BY CYTOPLASMIC POLYADENYLATION DURING MEIOSIS • Gene expression • Gene regulation • Translational control of mRNAs • CPEBs & cytoplasmic polyadenylation • Meiosis and translational control of mRNAs mediated by CPEBs • CPEBs beyond meiosis…

  33. CPEBs BEYOND MEIOSIS… CPEBs are involved in local translation in dendrites CPEBs are required for long term memory CPEBs are involved in cell proliferation, angiogenesis… CPEB4 is involved in pancreatic adenocarcinoma

  34. Raúl Méndez Lab

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