Figure 10. Timing mechanisms controlling sexually dimorphic nervous system differentiation during sexual maturation.

(A) The evolutionarily conserved lin-28/let-7/lin-41 heterochronic pathway controls the timing of the expression of multiple neuron-specific effectors in the male nervous system. The RNA-binding protein LIN-28 controls the expression of the miRNA let-7, which in turn controls expression of the RNA-binding protein LIN-41. LIN-41 let-7-mediated downregulation at the onset of sexual maturation de-represses LIN-41 targets LIN29A, MAB-3 and DMD-3. Expression of these LIN-41 effectors in specific neurons in males, at the onset of sexual maturation, constitute effector modules directing the precisely timed nervous system masculinization. We hypothesize that similar LIN-41 effectors, not identified yet, could be acting in other neurons in the male nervous system and in the hermaphrodite nervous system. (B) Temporal, sex-specific and neuron-specific intersectional control of nervous system differentiation during sexual maturation. A hypothetical male neuron is shown. As discussed above, LIN-41 repression of the heterochronic pathway is relieved at the onset of sexual maturation, allowing neuron-specific effector proteins to be expressed. In males, degradation of the ubiquitously expressed transcriptional repressor TRA-1 allows expression of male-specific regulatory effectors (blue boxes same as panel A). The neuron type-specificity of regulatory effector gene expression is determined by terminal selector transcription factors that control the expression of many other neuronal identity features. Hence, terminal selectors define a neuron type-specific, but permissive state whose sex- and time-specificity is controlled by factors that antagonize the effect of terminal selectors on regulatory effector genes (transcriptionally – TRA-1; translationally – LIN-41). Note that features that are controlled by sex/time-specific regulatory effectors, exemplified by LIN-29A regulation of neurotransmitter pathway genes, are also controlled by terminal selectors, thereby constituting a ‘feedforward’ regulatory architecture.