Two microRNA regulatory circuits set start and end times for dendritic arborization of a nociceptive neuron
Abstract
Choreographic dendritic arborization takes place within a defined time frame, but the timing mechanism is currently not known. Here, we report that a precisely timed lin-4-lin-14 regulatory circuit triggers an initial dendritic growth activity whereas a precisely timed let-7-lin-41 regulatory circuit signals a subsequent developmental decline in dendritic growth ability, hence restricting dendritic arborization within a defined time frame. Loss-of-function mutations in the lin-4 microRNA gene cause limited dendritic outgrowth whereas loss-of-function mutations in its direct target, the lin-14 transcription factor gene, cause precocious and excessive outgrowth. In contrast, loss-of-function mutations in the let-7 microRNA gene prevent a developmental decline in dendritic growth ability whereas loss-of-function mutations in its direct target, the lin-41 tripartite motif protein gene, cause further decline. lin-4 and let-7 regulatory circuits are expressed at the right place and the right time to set start and end times for PVD dendritic arborization. Replacing the endogenous lin-4 promoter at the lin-4 locus with a late-onset let-7 promoter delays PVD dendrite arborization whereas replacing the endogenous let-7 promoter at the let-7 locus with an early-onset lin-4 promoter causes precocious decline in dendritic growth ability in PVD neurons. We further find that lin-28 acts upstream of let-7 in regulating developmental decline in dendritic growth ability. Our results indicate that the lin-4-lin-14 and the lin-28-let-7-lin-41 regulatory circuits control the timing of PVD dendrite arborization through antagonistic regulation of the DMA-1 receptor level on PVD dendrites.
Additional Information
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. This version posted September 1, 2021. This work was funded by grants from the March of Dimes Foundation (C.C.), the Whitehall Foundation Research Award (C.C.), the National Science Foundation (IOS-1455758 to C.C.), the National Institute of General Medical Sciences of the National Institutes of Health (R01GM111320 to C.C.), and the Howard Hughes Medical Institute (K.S.). We thank Daniel J. Dickinson and Bob Goldstein for providing reagents and CRISPR protocols, David H.A. Fitch for the lep-5(ny28) mutant allele, Oliver Hobert for the lin-29(xe61) reporter strain, Kana Hamada for confocal imaging protocols, Evguenia Ivakhnitskaia for technical assistance and critical reading the manuscript, the Caenorhabditis Genetics Center for strains, and the WormBase for readily accessible information. Author Contributions: N.S. conceived, designed, performed, analyzed experiments, made constructs, and drafted the article. H.C. conceived, designed, performed, analyzed experiments, and drafted the article. Y.Z. conceived, designed, performed, analyzed experiments, and made constructs. M.S. made the promoter replacement CRISPR lines, performed, and analyzed experiments. W.Z. made the dma-1(wy996) [dma-1::YFP] CRISPR line and contributed unpublished essential data and reagents. K.S. conceived experiments, contributed unpublished essential data and reagents, and drafted the article. C.C. conceived, designed, analyzed and interpreted data, and drafted the article. The authors declare no competing interests.Attached Files
Submitted - 2021.08.31.458402v1.full.pdf
Supplemental Material - media-1.pdf
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Additional details
- Eprint ID
- 110701
- Resolver ID
- CaltechAUTHORS:20210902-200800060
- March of Dimes Foundation
- Whitehall Foundation
- IOS-1455758
- NSF
- R01GM111320
- NIH
- Howard Hughes Medical Institute (HHMI)
- Created
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2021-09-02Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field