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

许多脊椎动物雄性和雌性之间的身体结构存在差异，称为性二态性，传统上认为这是由雌激素和睾酮激素调节的。 最近的一些证据表明，维生素A的分子类似物称为类维生素A，包括代谢物视黄酸，也在许多内分泌途径中发挥作用。 视黄酸通过与细胞核中的分子受体分子结合来发挥其作用。 这种结合激活复杂的程序，包括发育，细胞分化和细胞死亡，并被认为控制同源框基因的顺序表达，这是至关重要的发展模式的时间。 一个中心问题是视黄酸的量在发育过程中是如何在空间和时间上控制的。 本研究以一种硬骨鱼为模型，其胚胎发育后在骨骼结构和脊髓中具有显著的两性异形。 这些假设是：第一，视黄酸在神经系统的脊髓中差异合成和分解代谢;第二，视黄酸的随后梯度为产生特定椎骨、脊神经节和脊髓内运动神经元的性别特异性模式的基因的发育控制建立坐标。 生物化学和分子方法用于确定两种特定酶何时、何地以及如何控制视黄酸的合成（视黄醇脱氢酶，RALDH）和降解（视黄酸羟化酶，CYP 26），从而允许操纵视黄酸以研究其作用。 结果有望首次建立视黄酸和性二态胚胎后发育和身体计划和神经系统分化之间的联系。 这些发现将对神经内分泌学以外的发育生物学和生理学产生影响。 其他影响来自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）的州立机构中培训主要来自代表性不足群体的学生。

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)