Sexually Dimorphic unc-6/Netrin Expression Controls Sex-Specific Maintenance of Synaptic Connectivity

Peter Weinberg, Matthew Berkseth, David Zarkower, Oliver Hobert

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Nervous systems display intriguing patterns of sexual dimorphisms across the animal kingdom, but the mechanisms that generate such dimorphisms remain poorly characterized. In the nematode Caenorhabditis elegans, a number of neurons present in both sexes are synaptically connected to one another in a sexually dimorphic manner as a result of sex-specific synaptic pruning and maintenance [1–3]. We define here a mechanism for the male-specific maintenance of the synaptic connections of the phasmid sensory neuron PHB and its male-specific target, the sex-shared AVG interneuron. We show that the C. elegans Netrin ortholog UNC-6, signaling through its cognate receptor UNC-40/DCC and the CED-5/DOCK180 guanine nucleotide exchange factor, is both required and sufficient for male-specific synaptic maintenance. The dimorphism of unc-6 activity is brought about by sex-specific regulation of unc-6 transcription. Although unc-6 is transcribed in the AVG neuron of males and hermaphrodites during juvenile stages, unc-6 expression is downregulated in AVG in hermaphrodites during sexual maturation but is maintained during sexual maturation of males. unc-6 downregulation in hermaphrodites is conferred by the master regulator of hermaphrodite sexual identity, the Gli/CI homolog TRA-1, which antagonizes the non-sex-specific function of the LIM homeobox gene lin-11, a terminal selector and activator of unc-6 in AVG. Preventing the downregulation of unc-6 in AVG of hermaphrodites through ectopic expression of unc-6 in transgenic animals results in the maintenance of the PHB>AVG synapses in hermaphrodites. Taken together, intersectional transcriptional regulation of unc-6/Netrin is required and sufficient to cell autonomously pattern sexually dimorphic synapses. Weinberg et al. show that the unc-6/Netrin system is required and sufficient to maintain male-specific synaptic connectivity of two sex-shared neurons. Sex specificity of unc-6 function is ensured by sex-specific transcription of unc-6 via a sex-specific transcription factor collaborating with a cell-specific terminal selector of neuronal identity.

Original languageEnglish (US)
Pages (from-to)623-629.e3
JournalCurrent Biology
Volume28
Issue number4
DOIs
StatePublished - Feb 19 2018

Bibliographical note

Funding Information:
We thank Qi Chen for generating transgenic lines, Meital Oren-Suissa for reagents and advice, Kelly Howell for generating the unc-6 and unc-40 reporter fosmids, Lori Glenwinkel for assistance with TargetOrtho, and the NIH for funding ( 2R37NS039996 to O.H.; 5R01GM053099 to D.Z.; and T32HD007480 to M.B.). Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs ( P40 OD010440 ). O.H. is an Investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • C. elegans
  • Netrin
  • sexual dimorphisms
  • transcriptional regulation

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