Abstract
Robust organismal development relies on temporal coordination of disparate physiological processes. In Caenorhabditis elegans, the heterochronic pathway controls a timely juvenile-to-adult (J/A) transition. This regulatory cascade of conserved proteins and small RNAs culminates in accumulation of the transcription factor LIN-29, which triggers coordinated execution of transition events. We report that two LIN-29 isoforms fulfill distinct functions. Functional specialization is a consequence of distinct isoform expression patterns, not protein sequence, and we propose that distinct LIN-29 dose sensitivities of the individual J/A transition events help to ensure their temporal ordering. We demonstrate that unique isoform expression patterns are generated by the activities of LIN-41 for lin-29a, and of HBL-1 for lin-29b, whereas the RNA-binding protein LIN-28 coordinates LIN-29 isoform activity, in part by regulating both hbl-1 and lin-41. Our findings reveal that coordinated transition from juvenile to adult involves branching of a linear pathway to achieve timely control of multiple events.
Highlights
Temporal coordination of diverse events is a hallmark of organismal development
Regulation of LIN-29 by let-7 and LIN-41 is dispensable for triggering seam cell fusion
A model of simple linear control in the heterochronic pathway predicts that lin-29(0) mutations cause the same phenotypes as upstream mutations that impair the activation of lin-29, such as let-7(0)
Summary
Temporal coordination of diverse events is a hallmark of organismal development This is illustrated by the juvenile-to-adult (J/A) transition of animals, in mammals known as puberty. In C. elegans, J/A transition is controlled by a cascade of regulators termed the heterochronic pathway, which coordinates somatic cell fate programs (Ambros and Horvitz, 1984). Let-7 mutations do not recapitulate all phenotypes of lin-29(0) (Ambros, 1989), as let-7 appears dispensable for proper timing of seam cell fusion (Hunter et al, 2013). We address these discrepancies by studying the regulation of the two LIN-29 isoforms and their functions in J/A transition. Our findings help to reframe the regulatory logic that enables the heterochronic pathway to coordinate different events into an overall larval-to-adult transition program
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