Department of Biological Sciences, Columbia University, Howard Hughes Medical Institute, New York, NY 10027, USA.
Department of Biological Sciences, Columbia University, Howard Hughes Medical Institute, New York, NY 10027, USA.
Curr Biol. 2017 Jan 23;27(2):199-209. doi: 10.1016/j.cub.2016.11.045. Epub 2017 Jan 5.
Functional and anatomical sexual dimorphisms in the brain are either the result of cells that are generated only in one sex or a manifestation of sex-specific differentiation of neurons present in both sexes. The PHC neuron pair of the nematode C. elegans differentiates in a strikingly sex-specific manner. In hermaphrodites the PHC neurons display a canonical pattern of synaptic connectivity similar to that of other sensory neurons, but in males PHC differentiates into a densely connected hub sensory neuron/interneuron, integrating a large number of male-specific synaptic inputs and conveying them to both male-specific and sex-shared circuitry. We show that the differentiation into such a hub neuron involves the sex-specific scaling of several components of the synaptic vesicle machinery, including the vesicular glutamate transporter eat-4/VGLUT, induction of neuropeptide expression, changes in axonal projection morphology, and a switch in neuronal function. We demonstrate that these molecular and anatomical remodeling events are controlled cell autonomously by the phylogenetically conserved Doublesex homolog dmd-3, which is both required and sufficient for sex-specific PHC differentiation. Cellular specificity of dmd-3 action is ensured by its collaboration with non-sex-specific terminal selector-type transcription factors, whereas the sex specificity of dmd-3 action is ensured by the hermaphrodite-specific transcriptional master regulator of hermaphroditic cell identity tra-1, which represses the transcription of dmd-3 in hermaphrodite PHC. Taken together, our studies provide mechanistic insights into how neurons are specified in a sexually dimorphic manner.
大脑中的功能和解剖性别二态性要么是仅在一种性别中产生的细胞的结果，要么是两性中存在的神经元性别特异性分化的表现。线虫 C. elegans 的 PHC 神经元以一种惊人的性别特异性方式分化。在雌雄同体中，PHC 神经元显示出与其他感觉神经元相似的典型突触连接模式，但在雄性中，PHC 分化为一个密集连接的中枢感觉神经元/中间神经元，整合大量雄性特异性突触输入，并将其传递到雄性特异性和性别共享的电路中。我们表明，这种中枢神经元的分化涉及突触囊泡机制的几个成分的性别特异性缩放，包括囊泡谷氨酸转运体 eat-4/VGLUT、神经肽表达的诱导、轴突投射形态的变化以及神经元功能的转变。我们证明这些分子和解剖重塑事件由进化上保守的性别二态性 Doublesex 同源物 dmd-3 自主控制，dmd-3 对于性别特异性 PHC 分化既需要又充分。dmd-3 作用的细胞特异性由其与非性别特异性末端选择器型转录因子的合作来确保，而 dmd-3 作用的性别特异性由雌雄同体特异性转录因子 tra-1 来确保，tra-1 抑制雌雄同体 PHC 中 dmd-3 的转录。总之，我们的研究提供了机制上的见解，说明神经元如何以性别二态的方式被指定。
