Genetic control of developmental timing

Univ Of Massachusetts Med Sch Worcester, Worcester MA

Investigators

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Abstract

1 Project Summary/Abstract Development of even the simplest of multicellular animals is astonishingly complex, involving the spatial and temporal orchestration of cellular proliferation, differentiation, and morphogenesis throughout the developing organism. The success of the species demands that its developmental programs are robust and resilient in the face of environmental and physiological perturbations – ‘everyday stresses’ that the developing animal’s circumstances routinely present. We study how genetic regulatory networks (GRNs) control temporal patterns of developmental events in animals, with an emphasis on understanding how microRNAs and other post-transcriptional regulators contribute to the robustness and stress resilience of animal development. We have worked primarily with the nematode Caenorhabditis elegans (C. elegans), studying a set of genes (the ‘heterochronic genes’) whose products function in a GRN that controls the timing of developmental cell fate transitions during larval development. At the core of the heterochronic GRN is the developmentally dynamic deployment of transcription factors that specify stage-specific cell fates for diverse cell types, under the control of microRNAs and RBPs that regulate the precisely timed changes in the levels of those transcription factors. C. elegans developmental timing offers an advantageous system to study developmental robustness, owing to the remarkably invariant cell lineage development of the wild type despite the free-living lifestyle of larvae, who grow up ‘in the wild’ foraging in the soil for microbial food. Consistent with roles for microRNAs in developmental robustness, the phenotypes of microRNA gene mutants are often conditional -- modifiable by environmental or physiological stresses that have no impact on wild type developmental fidelity. Our aim for the next 5 years is to advance mechanistic understanding of how microRNAs collaborate with other noncoding RNAs and RNA binding proteins (RBPs) to enable stress-robust specification of developmental cell fates. Our research plan will continue to leverage C. elegans developmental timing for discovery and characterization of how microRNAs collaborate with other regulators to enable stress-robust heterochronic GRN functionality. We also have added new elements to our research, involving the study of microRNAs in whole-body regeneration of the Acoel worm, Hofstenia miamia (H. miamia). The capacity for tissue replacement and regeneration is essentially universal across multicellular animals, presumably reflecting evolutionary roots in mechanisms of whole-body regeneration possessed by our ancient bilaterian ancestor. We view whole body regeneration as a particularly stressful context for an animal, involving as it does abrupt changes in gene expression, proliferation, and cell fate specification. We anticipate that new understanding of evolutionarily ancient functions of microRNAs in stress robustness can emerge from these H. miamia studies of whole-body regeneration.