Abstract
Prior to the meiotic divisions, dynamic chromosome reorganizations including pairing, synapsis, and recombination of maternal and paternal chromosome pairs must occur in a highly regulated fashion during meiotic prophase. How chromosomes identify each other's homology and exclusively pair and synapse with their homologous partners, while rejecting illegitimate synapsis with non-homologous chromosomes, remains obscure. In addition, how the levels of recombination initiation and crossover formation are regulated so that sufficient, but not deleterious, levels of DNA breaks are made and processed into crossovers is not understood well. We show that in Caenorhabditis elegans, the highly conserved Serine/Threonine protein phosphatase PP4 homolog, PPH-4.1, is required independently to carry out four separate functions involving meiotic chromosome dynamics: (1) synapsis-independent chromosome pairing, (2) restriction of synapsis to homologous chromosomes, (3) programmed DNA double-strand break initiation, and (4) crossover formation. Using quantitative imaging of mutant strains, including super-resolution (3D-SIM) microscopy of chromosomes and the synaptonemal complex, we show that independently-arising defects in each of these processes in the absence of PPH-4.1 activity ultimately lead to meiotic nondisjunction and embryonic lethality. Interestingly, we find that defects in double-strand break initiation and crossover formation, but not pairing or synapsis, become even more severe in the germlines of older mutant animals, indicating an increased dependence on PPH-4.1 with increasing maternal age. Our results demonstrate that PPH-4.1 plays multiple, independent roles in meiotic prophase chromosome dynamics and maintaining meiotic competence in aging germlines. PP4's high degree of conservation suggests it may be a universal regulator of meiotic prophase chromosome dynamics.
Highlights
For a single diploid genome to be partitioned into two haploid genomes in meiosis, chromosomes must undergo a sequence of strictly regulated dynamic events during meiotic prophase
We observed meiosis in the nematode Caenorhabditis elegans to examine the role of Protein Phosphatase 4 (PP4)
We have discovered that four essential steps in meiotic prophase require PPH-4.1 activity: (1) synapsis-independent chromosome pairing, (2) prevention of nonhomologous synapsis, (3) programmed double-strand breaks (DSBs) initiation, and (4) post-DSB CO formation
Summary
For a single diploid genome to be partitioned into two haploid genomes in meiosis, chromosomes must undergo a sequence of strictly regulated dynamic events during meiotic prophase. Chromosomes must encounter, assess homology, and form close pairing interactions with their homologous partners, to the exclusion of all other chromosomes. This pairing must be locked in through synapsis, or the assembly of the synaptonemal complex (SC), which is an intricate protein polymer running the length of each chromosome. Varying levels of homologous alignment can be observed prior to DSB formation in several organisms [2]. In Caenorhabditis elegans and Drosophila melanogaster, homologous chromosomes pair and synapse in the complete absence of recombination [3,4]. Levels of DSB formation must be tightly regulated, since creating either too many or too few DSBs is deleterious to the completion of meiosis
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