PT  - JOURNAL ARTICLE
AU  - Laura Pereira
AU  - Florian Aeschimann
AU  - Chen Wang
AU  - Hannah Lawson
AU  - Esther Serrano-Saiz
AU  - Douglas S. Portman
AU  - Helge Großhans
AU  - Oliver Hobert
TI  - Timing mechanism of sexually dimorphic nervous system differentiation
AID  - 10.1101/416735
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 416735
4099  - http://biorxiv.org/content/early/2018/09/13/416735.short
4100  - http://biorxiv.org/content/early/2018/09/13/416735.full
AB  - 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 several 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 embryonically born, sex-shared neurons is independent of the gonad, but is tightly coupled to the heterochronic pathway that was shown to control the timing of epidermal cell lineage division patterns. Sexually dimorphic differentiation of postmitotic neurons in the male nervous system is abrogated in animals that carry a mutation in the heterochronic 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 Zn finger transcription factor, lin-29a, is a critical target of LIN-41 in controlling sexual maturation of sex-shared neurons. Temporally controlled lin-29a is expressed in a male-specific manner in a subset of sex-shared neurons. 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 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.