Genetic dissection of crossover mutants defines discrete intermediates in mouse meiosis.

Crossovers (COs), the exchange of homolog arms, are required for accurate chromosome segregation during meiosis. Studies in yeast have described the single-end invasion (SEI) intermediate: a stabilized 3' end annealed with the homolog as the first detectible CO precursor. SEIs are thought to differentiate into double Holliday junctions (dHJs) that are resolved by MutLgamma (MLH1/MLH3) into COs. Currently, we lack knowledge of early steps of mammalian CO recombination or how intermediates are differentiated in any organism. Using comprehensive analysis of recombination in thirteen different genetic conditions with varying levels of compromised CO resolution, we infer CO precursors include asymmetric SEI-like intermediates and dHJs in mouse. In contrast to yeast, MLH3 is structurally required to differentiate CO precursors into dHJs. We verify conservation of aspects of meiotic recombination and show unique features in mouse, providing mechanistic insight into CO formation.

Maintenance of neuronal identity in C. elegans and beyond: Lessons from transcription and chromatin factors.

Neurons are remarkably long-lived, non-dividing cells that must maintain their functional features (e.g., electrical properties, chemical signaling) for extended periods of time - decades in humans. How neurons accomplish this incredible feat is poorly understood. Here, we review recent advances, primarily in the nematode C. elegans, that have enhanced our understanding of the molecular mechanisms that enable post-mitotic neurons to maintain their functionality across different life stages. We begin with "terminal selectors" - transcription factors necessary for the establishment and maintenance of neuronal identity. We highlight new findings on five terminal selectors (CHE-1 [Glass], UNC-3 [Collier/Ebf1-4], LIN-39 [Scr/Dfd/Hox4-5], UNC-86 [Acj6/Brn3a-c], AST-1 [Etv1/ER81]) from different transcription factor families (ZNF, COE, HOX, POU, ETS). We compare the functions of these factors in specific neuron types of C. elegans with the actions of their orthologs in other invertebrate (D. melanogaster) and vertebrate (M. musculus) systems, highlighting remarkable functional conservation. Finally, we reflect on recent findings implicating chromatin-modifying proteins, such as histone methyltransferases and Polycomb proteins, in the control of neuronal terminal identity. Altogether, these new studies on transcription factors and chromatin modifiers not only shed light on the fundamental problem of neuronal identity maintenance, but also outline mechanistic principles of gene regulation that may operate in other long-lived, post-mitotic cell types.

Maintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism.

Hox transcription factors play fundamental roles during early patterning, but they are also expressed continuously, from embryonic stages through adulthood, in the nervous system. However, the functional significance of their sustained expression remains unclear. In C. elegans motor neurons (MNs), we find that LIN-39 (Scr/Dfd/Hox4-5) is continuously required during post-embryonic life to maintain neurotransmitter identity, a core element of neuronal function. LIN-39 acts directly to co-regulate genes that define cholinergic identity (e.g., unc-17/VAChT, cho-1/ChT). We further show that LIN-39, MAB-5 (Antp/Hox6-8) and the transcription factor UNC-3 (Collier/Ebf) operate in a positive feedforward loop to ensure continuous and robust expression of cholinergic identity genes. Finally, we identify a two-component design principle for homeostatic control of Hox gene expression in adult MNs: Hox transcriptional autoregulation is counterbalanced by negative UNC-3 feedback. These findings uncover a noncanonical role for Hox proteins during post-embryonic life, critically broadening their functional repertoire from early patterning to the control of neurotransmitter identity.