Mechanisms of Developmental Fidelity

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 DESCRIPTION (provided by applicant): Developing embryos face vast numbers of parallel and sequential decisions each that is confronted with fluctuating environments and molecular "noise," and is thus fraught with a certain rate of error. While quality control systems that corret decision-making errors must be pervasive and are critical for human development, almost nothing is known about them. The hypothesis driving the proposed studies is that there exist quality control systems operating during development that ensure high-fidelity outcomes and that such systems may function across disparate developmental processes. We will avail of the highly reproducible development of C. elegans to investigate the mechanisms that regulate developmental fidelity. We found that C. elegans males show frequent "errors" in the activation of programmed cell death (PCD) during formation of the tail ray sensory structures and in the left-right (L/R) orientation of the major organs and that the propensity for these errors differs widely between different wild isolates (isotypes). Isotypes with high error rates in these two processes ("low-fidelity" strains) also show high variance in other processes, including germline stem cell proliferation and L1 larval length. In contrast, a strain with low error rates ("high-fidelity") in the former traits also shows low variance in the latter. We propose to unveil the molecular genetic basis for stochastic PCD and errors in L/R handedness and to investigate whether the fidelity of different developmental processes might be influenced by common mechanisms, through two aims. In Aim 1, we will investigate whether variation in fidelity is fully independent or significantly co-varies across several developmental processes by analyzing errors in disparate developmental processes across 97 isotypes and recombinant inbred lines (RILs) derived from "high-" and "low-fidelity" isotypes. We will evaluate whether fidelity has an impact on other functions including growth and longevity. In Aim 2, we will identify the molecular genetic basis for variation in developmental errors/fidelity in PCD and L/R organ handedness and other events. While the high-risk/high-gain aspect of the proposed studies make them appropriate for the R21 mechanism, important results relevant to stochasticity of PCD and dysregulation of L/R organ asymmetry will be obtained regardless of the generality of fidelity-controlling mechanisms. The proposed studies promise to yield new information regarding regulatory mechanisms underlying birth defects and dysregulation of cell proliferation, including in cancer. In addition, uncovering mechanisms that lead to inappropriate, stochastic cell death may provide important insights into sporadic cell death in neurodegenerative diseases.