Environmental regulation of spinal cord development

脊髓发育的环境调节

• 批准号: 1754340
• 负责人: Laura Borodinsky
• 金额: $ 120万
• 依托单位: University of California-Davis
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1754340&HistoricalAwards=false
• 关键词: Environmental; regulation; spinal; cord; development

During development, the cells that form the brain need to produce many different kinds of neurons in order to generate the complicated neural circuits found in adults, a process called differentiation. Many different molecules affect the patterning of the embryonic nervous system; these molecules have been used to identify biochemical pathways that are part of the developmental programs cells utilize to acquire their individual neuronal identities. However, the extent to which the environment intervenes in the functioning of this developmental program, is an understudied aspect of neural development. This research project documents ways in which nervous system development is dynamic and sensitive to the environment in which it occurs, challenging the idea of a predetermined, rigid genetic program that completely dictates the fate of neural cells before they are born. A mechanistic explanation for the observed plastic changes (that the environmental plasticity produces neural circuits that better match an individual's performance to the particular environment they develop in) is also tested. The research will assess the influence of temperature on neuronal differentiation in the embryonic frog spinal cord, and chart the mechanisms through which temperature differences change the sensorimotor behavior of developing tadpoles. Understanding these basic mechanisms of nervous system development will benefit society by contributing to knowledge about neurodevelopmental disorders and spinal cord regeneration. In addition, this project will establish an educational program at the K-12 school in Shriners Hospital for Children Northern California. Children are patients, mostly from low-income families; they will be offered a school program when they need to stay long-term at the Hospital, a non-profit organization that cares for the children at no cost. The project will expose these children to hands-on science activities and the scientific method. This investigation hypothesizes that environmental cues modulate embryonic calcium activity in developing neurons, thus regulating spinal neuron differentiation and the establishment of effective locomotor circuitry. Using a multidisciplinary approach, this study will identify the mechanisms by which environmental temperature modulates calcium-mediated spontaneous electrical activity resulting in specification of developing spinal neurons. The study hypothesizes that the cold-sensitive transient receptor potential cation channel M8 (TRPM8) contributes to the higher frequency calcium spike activity observed at cold temperatures. Pharmacological and genetic approaches will be implemented to assess the necessity and sufficiency of TRPM8 in cold temperature-induced changes in calcium activity. Differentiation and patterns of connectivity of sensory and motor neuron populations in animals grown at different temperatures after reaching identical tadpole stages will be examined by immunostaining and luciferase assay reporters. This investigation will determine the mechanisms underlying the changes in sensory and motor neuron differentiation by rescuing the temperature-driven phenotype through imposing counteracting approaches to the changes in calcium spike activity. To determine the consequences of the temperature-driven changes in neuronal differentiation on sensorimotor behavior and to test whether there is interaction between the temperature at which animals are grown and the sensorimotor performance, embryos will be raised at different temperatures until tadpole stages when the flexion reflex and the swimming pattern will be assessed at different temperatures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在发育过程中，形成大脑的细胞需要产生许多不同类型的神经元，以产生成人中发现的复杂神经回路，这一过程称为分化。许多不同的分子影响胚胎神经系统的模式;这些分子已被用于识别生化途径，这些生化途径是细胞用于获得其个体神经元身份的发育程序的一部分。然而，环境在多大程度上干预了这一发育程序的运作，是神经发育的一个未充分研究的方面。这个研究项目记录了神经系统发育是动态的，对它发生的环境敏感的方式，挑战了预先确定的，严格的遗传程序的想法，完全决定了神经细胞在出生前的命运。还测试了对所观察到的塑性变化的机械解释（即环境可塑性产生的神经回路更好地将个体的表现与他们所处的特定环境相匹配）。这项研究将评估温度对胚胎青蛙脊髓神经元分化的影响，并绘制温度差异改变发育中蝌蚪感觉运动行为的机制。了解神经系统发育的这些基本机制将有助于了解神经发育障碍和脊髓再生，从而造福社会。此外，该项目将在北方加州的施里纳儿童医院的K-12学校建立一个教育计划。儿童是病人，大多来自低收入家庭;当他们需要长期留在医院时，他们将获得一个学校计划，医院是一个免费照顾儿童的非营利组织。该项目将使这些儿童接触动手科学活动和科学方法。这项研究假设，环境的线索调节胚胎发育中的神经元钙的活动，从而调节脊髓神经元的分化和建立有效的运动回路。使用多学科的方法，本研究将确定的机制，环境温度调节钙介导的自发电活动，导致规格的发展脊髓神经元。该研究假设冷敏感瞬时受体电位阳离子通道M8（TRPM 8）有助于在低温下观察到的更高频率的钙峰活动。将实施药理学和遗传学方法来评估TRPM 8在低温诱导的钙活性变化中的必要性和充分性。将通过免疫染色和荧光素酶测定报告基因检查在达到相同蝌蚪阶段后在不同温度下生长的动物中感觉和运动神经元群体的分化和连接模式。这项调查将确定的感觉和运动神经元分化的变化的机制，通过挽救温度驱动的表型，通过施加抵消的方法，钙峰活性的变化。为了确定神经元分化的温度驱动变化对感觉运动行为的影响，并测试动物生长温度与感觉运动行为之间是否存在相互作用，胚胎将在不同的温度下培养，直到蝌蚪阶段，在不同的温度下评估屈曲反射和游泳模式。该奖项反映了NSF的法定使命，并已被视为通过使用基金会的知识价值和更广泛的影响审查标准进行评估，

项目成果

Calcium dynamics at the neural cell primary cilium regulate Hedgehog signaling-dependent neurogenesis in the embryonic neural tube.

• DOI: 10.1073/pnas.2220037120
• 发表时间: 2023-06-06
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Shim, Sangwoo;Goyal, Raman;Panoutsopoulos, Alexios A.;Balashova, Olga A.;Lee, David;Borodinsky, Laura N.
• 通讯作者: Borodinsky, Laura N.

Non-canonical Hedgehog signaling regulates spinal cord and muscle regeneration in Xenopus laevis larvae.

• DOI: 10.7554/elife.61804
• 发表时间: 2021-05-06
• 期刊: eLife
• 影响因子: 7.7
• 作者: Hamilton AM;Balashova OA;Borodinsky LN
• 通讯作者: Borodinsky LN

Pak1ip1 Loss-of-Function Leads to Cell Cycle Arrest, Loss of Neural Crest Cells, and Craniofacial Abnormalities

• DOI: 10.3389/fcell.2020.510063
• 发表时间: 2020-09
• 期刊: Frontiers in Cell and Developmental Biology
• 影响因子: 5.5
• 作者: A. Panoutsopoulos;Angelo Harlan De Crescenzo;Albert Lee;A. M. Lu;A. Ross;L. N. Borodinsky;R. Marcucio;P. Trainor;K. Zarbalis