Retinoic Acid: A Link Between Body Plan and Neural Sexual Dimorphism

许多脊椎动物在雄性和雌性之间产生了身体结构上的差异，即所谓的性别二型性，传统上被认为是由激素雌激素和睾丸素调节的。最近的一些证据表明，被称为维甲酸的维生素A的分子类似物，包括代谢物维甲酸，也在许多内分泌途径中发挥作用。维甲酸通过与细胞核中的分子受体分子结合而发挥作用。这种结合激活了包括发育、细胞分化和细胞死亡在内的复杂程序，并被认为控制着同源盒基因的顺序表达，而同源盒基因在发育模式的选择上至关重要。一个核心问题是，在发育过程中，维甲酸的数量是如何在空间和时间上受到控制的。这个项目使用一种硬骨鱼作为模型，这种硬骨鱼在胚胎后发育，在骨骼结构和脊髓中具有明显的性别二型性。第一个假设是，维甲酸在神经系统的脊髓中以不同的方式合成和分解，第二，随之而来的维甲酸梯度为发育控制基因建立了坐标，这些基因产生了特定脊椎、脊神经节和脊髓内运动神经元的性别特异性模式。生化和分子方法被用来确定两种特定的酶何时、何地以及如何控制维甲酸的合成(视黄醛脱氢酶，RALDH)和降解(维甲酸羟基酶，CYP26)，从而允许操纵维甲酸来研究其影响。研究结果有望首次确定维甲酸与胚胎后性二态发育以及身体计划和神经系统的分化之间的联系。这些发现将产生从神经内分泌学到发育生物学和生理学的影响。其他影响来自于促进来自代表性不足群体的年轻科学家的职业生涯，以及在有资格参加刺激竞争性研究实验计划(EPSCoR)的州立机构中培训学生，这些学生也主要来自代表性不足的群体

Many vertebrate animals develop differences in body structure between males and females, known as sexual dimorphism, which traditionally is considered to be regulated by the hormones estrogen and testosterone. Some recent evidence shows that molecular analogs of vitamin A called retinoids, including the metabolite retinoic acid, also play a role in many endocrine pathways. Retinoic acid exerts its effects by binding to molecular receptor molecules in the cell nucleus. This binding activates complex programs including development, cell differentiation and cell death, and is thought to control sequential expression of the homeobox genes which are crucial in the timing of patterns of development. A central question is how amounts of retinoic acid are spatially and temporally controlled during development. This project uses as a model a teleost fish species with prominent post-embryonic development of a sexual dimorphism in skeletal structure and spinal cord. The hypotheses are first, that retinoic acid is differentially synthesized and catabolized in the spinal cord of the nervous system, and second, that the consequent gradients of retinoic acid establish coordinates for developmental control of genes producing the sex-specific pattern of particular vertebrae, spinal ganglia and motor neurons within the spinal cord. Biochemical and molecular approaches are used to determine when, where and how two specific enzymes control the synthesis (retinaldehyde dehydrogenase, RALDH) and degradation (retinoic acid hydroxylase, CYP26) of retinoic acid, thus allowing retinoic acid to be manipulated to study its effects. Results are expected to establish for the first time a link between retinoic acid and sexually dimorphic post-embryonic development and differentiation of the body plan and nervous system. The findings will have an impact beyond neuroendocrinology to developmental biology and physiology. Additional impacts come from promoting the career of a young scientist from an underrepresented group, and training students also largely from underrepresented groups, in a state institution eligible for the Experimental Program to Stimulate Competitive Research (EPSCoR)