meg-1

id: Q21126
gene_symbol: meg-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: 'MEG-1 (maternal-effect germ cell defective 1) is an intrinsically disordered,
  serine-rich protein that is a core component of P granules during embryonic germline
  segregation in C. elegans. MEG-1 is expressed maternally and localizes exclusively
  to P granules from the 4-8 cell stage through early embryogenesis, with expression
  diminishing at the 100-cell stage. The protein functions redundantly with MEG-2
  to regulate P granule dynamics through phosphorylation-dependent phase transitions:
  phosphorylation by MBK-2/DYRK kinase promotes granule disassembly in anterior cytoplasm,
  while dephosphorylation by PP2A(PPTR-1/2) promotes assembly in posterior cytoplasm.
  MEG-1 is essential for proper P granule segregation during embryonic cell divisions,
  germ cell proliferation during larval development, and ultimately fertility. Loss
  of meg-1 causes P granule mis-segregation, underproliferation of larval germ cells,
  aberrant P granule morphology, and sterility. MEG-1 localization to P granules depends
  on the membrane-bound protein MES-1.'
existing_annotations:
  - term:
      id: GO:0036093
      label: germ cell proliferation
    evidence_type: IGI
    original_reference_id: PMID:25535836
    review:
      summary: MEG-1 is required for germ cell proliferation during larval 
        development. meg-1 mutants show underproliferation of germ cells 
        (PMID:18202375). The IGI annotation with meg-3 and meg-4 reflects that 
        MEG proteins contribute redundantly to germ cell viability and 
        proliferation (PMID:25535836, PMID:21305687). MEG-1 may function with 
        nanos family members nos-2 and nos-3 to promote germ cell proliferation.
      action: ACCEPT
      reason: This annotation is well-supported by multiple publications. 
        PMID:18202375 states that meg-1 mutants exhibit underproliferation in 
        larval germ cells. PMID:25535836 demonstrates that MEG proteins are 
        required redundantly for fertility and germ cell development. The IGI 
        evidence from genetic interactions with other MEG family members is 
        appropriate.
      supported_by:
        - reference_id: PMID:18202375
          supporting_text: 'meg-1 mutants exhibit multiple germline defects: P-granule
            mis-segregation in embryos, underproliferation and aberrant P-granule
            morphology in larval germ cells, and ultimately, sterility as adults'
        - reference_id: PMID:25535836
          supporting_text: The MEG (maternal-effect germline defective) proteins
            are germ plasm components that are required redundantly for 
            fertility
  - term:
      id: GO:1903864
      label: P granule disassembly
    evidence_type: IGI
    original_reference_id: PMID:25535836
    review:
      summary: MEG-1 in its phosphorylated form promotes P granule disassembly 
        in the anterior cytoplasm of pre-gastrulation embryos. This is a key 
        function of MEG proteins - phosphorylation by MBK-2 promotes granule 
        disassembly while dephosphorylation promotes assembly (PMID:25535836). 
        The annotation is supported by the finding that MEG-1 and MEG-2 
        knockdown results in defective P granule disassembly in anterior 
        cytoplasm.
      action: ACCEPT
      reason: This annotation accurately captures a specific aspect of MEG-1 
        function. The phosphorylated form of MEG-1 promotes P granule 
        disassembly. While MEG-1 also promotes assembly in its dephosphorylated 
        form, the disassembly annotation is correct and well-supported by 
        experimental evidence showing defective disassembly upon MEG-1/MEG-2 
        knockdown.
      supported_by:
        - reference_id: PMID:25535836
          supporting_text: Phosphorylation of the MEGs promotes granule 
            disassembly and dephosphorylation promotes granule assembly
        - reference_id: file:worm/meg-1/meg-1-uniprot.txt
          supporting_text: Simultaneous RNAi-mediated knockdown of meg-1 and 
            meg-2 results in defects in P granule disassembly in the anterior 
            cytoplasm of the P1 blastomere causing some P granules to be 
            mis-segregated to somatic blastomeres
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25535836
    review:
      summary: MEG-1 has documented physical interactions with PPTR-1, PPTR-2 
        (PP2A regulatory subunits), and PGL-1 (a P granule component) based on 
        PMID:25535836. However, 'protein binding' (GO:0005515) is an 
        uninformative annotation that does not describe the molecular function.
      action: MODIFY
      reason: GO curation guidelines recommend avoiding generic 'protein 
        binding' annotations when more specific terms are available. MEG-1 
        interacts with phosphatase subunits PPTR-1/PPTR-2 and with P granule 
        component PGL-1. More informative annotations would be phosphatase 
        binding or RNA granule component binding if such terms exist. 
        Alternatively, this should be removed as uninformative.
      proposed_replacement_terms:
        - id: GO:0019903
          label: protein phosphatase binding
      supported_by:
        - reference_id: file:worm/meg-1/meg-1-uniprot.txt
          supporting_text: Interacts with pptr-1, pptr-2 and pgl-1
        - reference_id: PMID:25535836
          supporting_text: Regulation of RNA granule dynamics by phosphorylation
            of serine-rich, intrinsically disordered proteins in C.
  - term:
      id: GO:0043186
      label: P granule
    evidence_type: IDA
    original_reference_id: PMID:18202375
    review:
      summary: MEG-1 localizes to P granules during embryonic germline 
        segregation. This is a core finding from PMID:18202375 where MEG-1 and 
        MEG-2 were first characterized as P granule components. The protein is 
        expressed in the P lineage from the 4-8 cell stage and localizes 
        exclusively to P granules during this developmental window.
      action: ACCEPT
      reason: This is a well-supported cellular component annotation with direct
        experimental evidence (IDA). PMID:18202375 clearly demonstrates that 
        MEG-1 encodes a protein that localizes exclusively to P granules during 
        embryonic germline segregation. The localization depends on MES-1.
      supported_by:
        - reference_id: PMID:18202375
          supporting_text: meg-1 and meg-2 (maternal-effect germ-cell 
            defective), which are expressed in the maternal germline and encode 
            proteins that localize exclusively to P granules during embryonic 
            germline segregation
        - reference_id: PMID:18202375
          supporting_text: Localization of MEG-1 to P granules depends upon the 
            membrane-bound protein MES-1
  - term:
      id: GO:1903863
      label: P granule assembly
    evidence_type: IGI
    original_reference_id: PMID:25535836
    review:
      summary: MEG-1 in its dephosphorylated form promotes P granule assembly in
        the posterior cytoplasm. This annotation is missing from the existing 
        GOA annotations but is equally supported by the literature as P granule 
        disassembly. PMID:25535836 clearly states that dephosphorylated MEG 
        proteins promote assembly.
      action: NEW
      reason: The current annotations include P granule disassembly but not P 
        granule assembly, despite MEG-1 being involved in both processes 
        depending on phosphorylation state. This annotation should be added to 
        provide a complete picture of MEG-1 function.
      supported_by:
        - reference_id: file:worm/meg-1/meg-1-uniprot.txt
          supporting_text: In its dephosphorylated form, and together with 
            meg-2, promotes the assembly and accumulation of zygotic P granules 
            in the posterior cytoplasm of pre-gastrulation embryos
        - reference_id: PMID:25535836
          supporting_text: Phosphorylation of the MEGs promotes granule 
            disassembly and dephosphorylation promotes granule assembly
  - term:
      id: GO:0030719
      label: P granule organization
    evidence_type: NAS
    review:
      summary: Added to align core_functions with existing annotations.
      action: NEW
      reason: Core function term not present in existing_annotations.
references:
  - id: PMID:18202375
    title: MEG-1 and MEG-2 are embryo-specific P-granule components required for
      germline development in Caenorhabditis elegans.
    findings:
      - statement: MEG-1 and MEG-2 are P granule components expressed in 
          maternal germline
        supporting_text: meg-1 and meg-2 (maternal-effect germ-cell defective), 
          which are expressed in the maternal germline and encode proteins that 
          localize exclusively to P granules during embryonic germline 
          segregation
      - statement: MEG proteins localize exclusively to P granules during 
          embryonic germline segregation
        supporting_text: encode proteins that localize exclusively to P granules
          during embryonic germline segregation
      - statement: MEG-1 localization depends on membrane-bound MES-1 protein
        supporting_text: Localization of MEG-1 to P granules depends upon the 
          membrane-bound protein MES-1
      - statement: meg-1 mutants show P granule mis-segregation, 
          underproliferation, aberrant morphology, and sterility
        supporting_text: 'meg-1 mutants exhibit multiple germline defects: P-granule
          mis-segregation in embryos, underproliferation and aberrant P-granule morphology
          in larval germ cells, and ultimately, sterility as adults'
      - statement: meg-1 provides critical link for germline continuity between 
          generations
        supporting_text: it provides a critical link for ensuring the continuity
          of germline development from one generation to the next
  - id: PMID:25535836
    title: Regulation of RNA granule dynamics by phosphorylation of serine-rich,
      intrinsically disordered proteins in C. elegans.
    findings:
      - statement: MEG proteins are intrinsically disordered, serine-rich 
          proteins
        supporting_text: a group of intrinsically disordered, serine-rich 
          proteins regulate the dynamics of P granules in C. elegans embryos
      - statement: MEG-1 and MEG-3 are substrates of MBK-2/DYRK kinase and PP2A 
          phosphatase
        supporting_text: MEG-1 and MEG-3 are substrates of the kinase MBK-2/DYRK
          and the phosphatase PP2A
      - statement: Phosphorylation promotes P granule disassembly; 
          dephosphorylation promotes assembly
        supporting_text: Phosphorylation of the MEGs promotes granule 
          disassembly and dephosphorylation promotes granule assembly
      - statement: MEG proteins are required redundantly for fertility
        supporting_text: The MEG (maternal-effect germline defective) proteins 
          are germ plasm components that are required redundantly for fertility
      - statement: P granules are non-homogeneous structures regulated by 
          phosphorylation
        supporting_text: despite their liquid-like behavior, P granules are 
          non-homogeneous structures whose assembly in embryos is regulated by 
          phosphorylation
  - id: PMID:21305687
    title: C. elegans meg-1 and meg-2 differentially interact with nanos family 
      members to either promote or inhibit germ cell proliferation and survival.
    findings:
      - statement: MEG-1 may function with NOS-2 and NOS-3 to promote germ cell 
          proliferation
        full_text_unavailable: true
      - statement: MEG-1 and MEG-2 have differential genetic interactions with 
          nanos family members
        full_text_unavailable: true
  - id: file:worm/meg-1/meg-1-uniprot.txt
    title: UniProt entry for MEG-1 (Q21126)
    findings:
      - statement: MEG-1 interacts with PPTR-1, PPTR-2, and PGL-1
        supporting_text: Interacts with pptr-1, pptr-2 and pgl-1
      - statement: In dephosphorylated form promotes P granule assembly in 
          posterior cytoplasm
        supporting_text: In its dephosphorylated form, and together with meg-2, 
          promotes the assembly and accumulation of zygotic P granules in the 
          posterior cytoplasm of pre-gastrulation embryos
      - statement: Double knockdown of meg-1 and meg-2 causes P granule 
          disassembly defects
        supporting_text: Simultaneous RNAi-mediated knockdown of meg-1 and meg-2
          results in defects in P granule disassembly in the anterior cytoplasm 
          of the P1 blastomere causing some P granules to be mis-segregated to 
          somatic blastomeres
core_functions:
  - description: MEG-1 is a core regulator of P granule dynamics during early 
      embryogenesis. Through phosphorylation-dependent phase transitions, MEG-1 
      controls both P granule assembly (in dephosphorylated state) and 
      disassembly (in phosphorylated state), ensuring proper asymmetric 
      segregation of P granules to germline blastomeres.
    molecular_function:
      id: GO:0019903
      label: protein phosphatase binding
    directly_involved_in:
      - id: GO:0030719
        label: P granule organization
      - id: GO:1903863
        label: P granule assembly
    locations:
      - id: GO:0043186
        label: P granule
    supported_by:
      - reference_id: PMID:25535836
        supporting_text: Phosphorylation of the MEGs promotes granule 
          disassembly and dephosphorylation promotes granule assembly
      - reference_id: PMID:18202375
        supporting_text: encode proteins that localize exclusively to P granules
          during embryonic germline segregation
  - description: MEG-1 is required for proper germ cell proliferation during 
      larval development, functioning redundantly with MEG-2 and potentially 
      with nanos family members NOS-2 and NOS-3.
    molecular_function:
      id: GO:0019903
      label: protein phosphatase binding
    directly_involved_in:
      - id: GO:0036093
        label: germ cell proliferation
    locations:
      - id: GO:0043186
        label: P granule
    supported_by:
      - reference_id: PMID:18202375
        supporting_text: 'meg-1 mutants exhibit multiple germline defects: P-granule
          mis-segregation in embryos, underproliferation and aberrant P-granule morphology
          in larval germ cells'
      - reference_id: PMID:25535836
        supporting_text: The MEG (maternal-effect germline defective) proteins 
          are germ plasm components that are required redundantly for fertility
suggested_questions:
  - question: What is the precise mechanism by which phosphorylation of MEG-1 
      promotes P granule disassembly in anterior cytoplasm?
    experts:
      - Geraldine Seydoux
  - question: How does MEG-1 coordinate with MEG-2, MEG-3, and MEG-4 to regulate
      P granule dynamics and germ cell fate?
    experts:
      - Valerie Reinke
      - Geraldine Seydoux
suggested_experiments:
  - experiment_type: Time-lapse imaging
    description: Use lattice light sheet microscopy to track GFP-MEG-1 dynamics 
      during early embryonic cell divisions with and without MBK-2 kinase 
      activity
    hypothesis: Phosphorylation by MBK-2 causes MEG-1 to dissociate from P 
      granules in anterior cytoplasm, promoting their disassembly
  - experiment_type: Phosphoproteomics
    description: Identify all phosphorylation sites on MEG-1 and determine which
      are regulated by MBK-2 vs PP2A using mass spectrometry
    hypothesis: Multiple serine residues in MEG-1's disordered regions are 
      differentially phosphorylated to regulate granule dynamics
tags:
  - caeel-p-granules