Components of the intricately timed maturation process occur independent of the individual’s experience and exposure to environmental stimuli, and suggest that cell-intrinsic genetic timer mechanisms coordinate the maturation of the nervous system. Leveraging the molecular and functional atlases that we previously generated, we characterized one genetic timer program, initiated by the microRNA (miRNA) lin-4 (ortholog of vertebrate miR-125) and subsequent repression of a downstream target, the transcription factor LIN-14, that broadly controls many, but not all, temporal gene expression changes. lin-4 is part of the heterochronic pathway, which is a cascade of regulatory miRNAs, transcription factors, and translational regulators that specifies the proper sequence of developmental events from the C. elegans larval stages to the adult in mitotic lineages (e.g., epithelial cells).
Genetic Timer of Neuronal Maturation
We demonstrated a widespread role for lin-4 in controlling post-mitotic neuronal maturation by regulating the progression of neuronal gene expression profiles across post-embryonic development: genetic manipulation of lin-4 and downstream pathway target, resulted in alteration in developmental-regulated neuropeptide expression patterns and consequent altered exploratory behavior across post-embryonic developmental transitions.
We are continuing to investigate additional components of the heterochronic pathway as well as using genetic and genomics approaches to identify novel genetic timers.
The genetic timer mechanisms, namely the heterochronic pathway including the microRNA lin-4 (vertebrate ortholog miR-125) that controls C. elegans post-embryonic development, are well-conserved in vertebrates, but have not been extensively characterized in vertebrate systems. We are interested address the following questions:
1) Are the regulatory mechanisms used by C. elegans and mice to control post-natal post-mitotic neuronal maturation evolutionarily conserved? If so, how are they employed on vastly different developmental timescales (the time from hatch to adulthood is 2.5 days for C. elegans and 2+ months for mice)?
2) What are the evolutionarily divergent regulatory mechanisms controlling neuronal maturation to address the vastly different developmental timescale and needs of the organisms?
We will combine candidate and unbiased genome-wide approaches across the two model organisms to establish a bi-directional, two-model translational research program.