Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gain-of-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development.

中文翻译：

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结节性硬化症（TSC）的神经发育发病机理。

结节性硬化症复合体（TSC）是一种了解大脑发育的模型疾病，因为已知导致TSC的基因，已鉴定出许多下游分子途径，并确定了由此引起的细胞事件扰动。因此，TSC提供了一个智力框架，以了解协调正常大脑发育的分子和生化途径。TSC1和TSC2基因编码形成GTPase激活蛋白（GAP）复合物的Hamartin和Tuberin。TSC基因（TSC1 / TSC2）中的失活突变导致持续的，富含雷帕霉素复合物1（mTORC1）靶标的哺乳动物同工型的大脑（RHEB）激活物中的Ras同源物。TOR是一种蛋白激酶，可调节整个自然界中许多生物的细胞大小。mTORC1抑制包括自噬在内的分解代谢过程，并激活包括mRNA翻译的合成代谢过程。mTORC1调节是通过两个主要的上游机制实现的。第一种机制是通过生长因子信号传导进行调节。第二种机制是氨基酸调节。导致mTORC1活性过高或过低的基因突变会导致一系列神经解剖学变化，范围从脑大小改变（微小和大头畸形）到皮质畸形到I型瘤形成。因为体细胞突变通常是这些变化的基础，所以突变的时间和位置会导致局灶性脑畸形。因此，这些突变 提供功能获得和功能丧失更改，这是评估开发过程中发生错误的事件并确定其功能生理后果的强大工具。关于TSC-mTORC1途径的知识使科学家能够预测哪些上游和下游突变会引起相应的神经解剖学变化。实际上，这些预测中的许多现在已经在临床上得到了验证。提供了与TSC实验室模型相关的临床影像学和组织化学结果的描述，使读者能够理解人类病理学如何能够提供对发育基本机制的理解。关于TSC-mTORC1途径的知识使科学家能够预测哪些上游和下游突变会引起相应的神经解剖学变化。实际上，这些预测中的许多现在已经在临床上得到了验证。提供了与TSC实验室模型相关的临床影像学和组织化学结果的描述，使读者能够理解人类病理学如何能够提供对发育基本机制的理解。关于TSC-mTORC1途径的知识使科学家能够预测哪些上游和下游突变会引起相应的神经解剖学变化。实际上，这些预测中的许多现在已经在临床上得到了验证。提供了与TSC实验室模型相关的临床影像学和组织化学结果的描述，使读者能够理解人类病理学如何能够提供对发育基本机制的理解。