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Timing mechanism of sexually dimorphic nervous system differentiation

Laura Pereira, Florian Aeschimann, Chen Wang, Hannah Lawson, Esther Serrano-Saiz, Douglas S Portman, Helge Grosshans, Oliver Hobert
doi: https://doi.org/10.1101/416735
Laura Pereira
Columbia University;
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Florian Aeschimann
Friedrich Miescher Institute for Biomedical Research;
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Chen Wang
Columbia University;
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Hannah Lawson
University of Rochester
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Esther Serrano-Saiz
Columbia University;
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Douglas S Portman
University of Rochester
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Helge Grosshans
Friedrich Miescher Institute for Biomedical Research;
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Oliver Hobert
Columbia University;
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  • For correspondence: or38@columbia.edu
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Abstract

In all animals, sexual differentiation of somatic tissue is precisely timed, yet the molecular mechanisms that control the timing of sexual differentiation, particularly in the brain, are poorly understood. We have used sexually dimorphic molecular, anatomical and behavioral features of the C. elegans nervous system to decipher a regulatory pathway that controls the precise timing of sexual differentiation. We find that the sexually dimorphic differentiation of postmitotic neurons in the male nervous system is abrogated in animals that carry a mutation in the miRNA let-7 and prematurely executed in animals either lacking the let-7 inhibitor lin-28, or the direct let-7 target lin-41, an RNA-binding, posttranscriptional regulator. We show that an isoform of a phylogenetically conserved transcription factor, lin-29a, is a critical target of LIN-41 in controlling sexual maturation of sex-shared neurons. lin-29a is expressed in a male-specific manner in a subset of sex-shared neurons at the onset of sexual maturation. lin-29a acts cell-autonomously in these neurons to control the expression of sexually dimorphic neurotransmitter switches, sensory receptor expression, neurite anatomy and connectivity, and locomotor behavior. lin-29a is not only required but also sufficient to impose male-specific features at earlier stages of development and in the opposite sex. The temporal, sexual and spatial specificity of lin-29a expression is controlled intersectionally through the lin-28/let-7/lin-41 heterochronic pathway, sex chromosome configuration and neuron type-specific terminal selector transcription factors. Two Doublesex-like transcription factors represent additional neuron-type specific targets of LIN-41 and are regulated in a similar intersectional manner, indicating the existence of modular outputs downstream of the heterochronic pathway. In conclusion, we have provided insights into the molecular logic of the timing of sexual differentiation in the C. elegans nervous system. Remarkably, the lin28/let7 axis also controls the timing of sexual differentiation in mice and humans thereby hinting toward a striking universality of the control mechanisms of sexual differentiation.

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Posted September 16, 2018.
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Timing mechanism of sexually dimorphic nervous system differentiation
Laura Pereira, Florian Aeschimann, Chen Wang, Hannah Lawson, Esther Serrano-Saiz, Douglas S Portman, Helge Grosshans, Oliver Hobert
bioRxiv 416735; doi: https://doi.org/10.1101/416735
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Timing mechanism of sexually dimorphic nervous system differentiation
Laura Pereira, Florian Aeschimann, Chen Wang, Hannah Lawson, Esther Serrano-Saiz, Douglas S Portman, Helge Grosshans, Oliver Hobert
bioRxiv 416735; doi: https://doi.org/10.1101/416735

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