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Glutamate Signaling Regulates Neural Tube Formation
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Glutamate Signaling Regulates Neural Tube Formation. |
| 개인저자 | Goyal, Raman. |
| 단체저자명 | University of California, Davis. Molecular, Cellular and Integrative Physiology. |
| 발행사항 | [S.l.]: University of California, Davis., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 70 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-04B. Dissertation Abstract International |
| ISBN | 9781392556054 |
| 학위논문주기 | Thesis (Ph.D.)--University of California, Davis, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Advisor: Borodinsky, Laura N. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Neural tube defects (NTDs) are one of the most common birth defects associated with the failure of the neural plate to fold and close, occurring in every 1 in 1,000 births in the US. The causes of NTDs are multiple and both genetic and environmental factors have been identified. Among these factors, the use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs by unknown mechanisms. In the mature nervous system, antiepileptic drugs decrease excitability by targeting diverse effectors. However, most studies have argued that off-target effects of these drugs are responsible for inducing NTDs in epileptic patients' offspring. Instead, the effect of AEDs on embryonic neural excitability remained mostly unexplored because of the prevailing view that neural activity is not apparent at neural plate stages. In contrast, I investigated whether neural activity plays a role in neural tube formation that is perturbed by AEDs. Indeed, my work demonstrates that glutamate signaling through NMDA receptors is present in the folding neural plate and is necessary for neural tube formation in Xenopus laevis embryos. Genetic and pharmacological downregulation of NMDA receptor function results in an increase in neural plate cell proliferation which impairs neural plate cell migration and folding during neurulation. Furthermore, incubation of neurulating embryos with AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued, with varied efficacy, by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. The mechanism of glutamate signaling in neural plate cells is unclear since synapses are not assembled yet at these early stages of development. In this study I investigated the molecular mechanisms by which glutamate is released and signals in the folding neural plate of Xenopus laevis embryos. I found that vesicular glutamate release from neural plate cells is necessary for neural tube formation. Released glutamate elicits calcium transients and activates ERK1/2 in neural plate cells. In turn, glutamate signaling appears to control expression and function of regulatory neural cell cycle proteins like Sox2, which is a pivotal transcription factor for modulating neural stem cell renewal and neurogenesis, depending on its level of expression and posttranslational modifications. My discoveries point out to the novel paradigm-shifting model in which neurotransmitter signaling is functional at neural plate stages and is crucial for the formation of the neural tube. Elucidating the features of neurotransmitter signaling during neural tube formation may identify AEDs that are safer during pregnancy. |
| 일반주제명 | Physiology. Developmental biology. Neurosciences. |
| 언어 | 영어 |
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