Chang Stephen
Department of Biochemistry, Stanford University School of Medicine, Beckman Center B400, 279 Campus Drive, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Curr Cardiol Rep. 2025 Aug 13;27(1):123. doi: 10.1007/s11886-025-02276-x.
Due to differences in cardiac structure and function, it has become increasingly clear that many aspects of cardiovascular anatomy, physiology, biochemistry, and disease are not well modeled in mice. This has spurred a search for new model organisms with the practical advantages of mice but that more closely mimic human biology and disease.
Until recently, little was known of lemur cardiovascular physiology, cell types, or pathology. In a recent trinity of papers, we established the mouse lemur (Microcebus spp.) - the world's smallest, most prolific, and among the most abundant non-human primates - and the cheapest and easiest to maintain, as a new tractable genetic model organism. In one of these studies, we conducted the first systematic phenotypic screen and classical genetic mapping in a non-human primate, leading to the identification and characterization of human-like cardiac arrhythmias. We successfully genetically mapped one familial lemur arrhythmia to a novel disease gene. In the other two studies, we built and applied a transcriptomic cell atlas for the mouse lemur, profiling 226,000 cells across 27 organs. This included the transcriptomic profiles of over 4000 cardiac cells, identifying 15 heart cell types that included several rare heart cell types. We documented the first null mutations in lemur, including nonsense mutations in three primate genes absent in mice, and exploited the atlas to reveal their transcriptional phenotypes, demonstrating the potential of the model organism along with synergy with the atlas. To propel these advances, we recently generated a new near telomere-to-telomere (T2T), phased diploid genome assembly for the mouse lemur, using a combination of short-, long-, and ultralong-read sequencing technologies - providing a foundational genomic resource to enhance gene and mutation discovery, functional genomics, and the applicability of cell atlas data in this new primate model. This review examines the mouse lemur (Microcebus species) as a new tractable genetic model organism for investigating primate-specific cardiovascular function and disease. Recent studies from our lab have laid a robust cellular, molecular, and genomic foundation for this model, including the first systematic phenotypic screens and classical genetic mapping in a non-human primate, showing that both forward and reverse genetic approaches are now feasible in lemurs. Collectively, these advances present a compelling case for the mouse lemur as a valuable and practical model organism for primate biomedical research.
由于心脏结构和功能的差异，越来越明显的是，心血管解剖学、生理学、生物化学和疾病的许多方面在小鼠中并未得到很好的模拟。这促使人们寻找具有小鼠实际优势但更能紧密模拟人类生物学和疾病的新型模式生物。
直到最近，人们对狐猴的心血管生理学、细胞类型或病理学了解甚少。在最近的三篇论文中，我们确立了小鼠狐猴（Microcebus spp.）——世界上最小、繁殖力最强且数量最多的非人类灵长类动物之一，也是最便宜且最易于饲养的动物——作为一种新的易于处理的遗传模式生物。在其中一项研究中，我们在一种非人类灵长类动物中进行了首次系统的表型筛选和经典遗传图谱绘制，从而鉴定并表征了类似人类的心律失常。我们成功地将一种家族性狐猴心律失常基因定位到一个新的疾病基因上。在另外两项研究中，我们构建并应用了小鼠狐猴的转录组细胞图谱，对27个器官中的226,000个细胞进行了分析。这包括4000多个心脏细胞的转录组图谱，鉴定出15种心脏细胞类型，其中包括几种罕见的心脏细胞类型。我们记录了狐猴中的首批无效突变，包括小鼠中不存在的三个灵长类基因中的无义突变，并利用该图谱揭示了它们的转录表型，证明了该模式生物的潜力以及与图谱的协同作用。为推动这些进展，我们最近利用短读长、长读长和超长读长测序技术的组合，为小鼠狐猴生成了一个新的近乎端粒到端粒（T2T）的、分阶段的二倍体基因组组装——提供了一个基础基因组资源，以加强基因和突变发现、功能基因组学以及该新灵长类模式中细胞图谱数据的适用性。本综述探讨了小鼠狐猴（Microcebus物种）作为一种用于研究灵长类动物特异性心血管功能和疾病的新的易于处理的遗传模式生物。我们实验室最近的研究为该模式奠定了坚实的细胞、分子和基因组基础，包括在一种非人类灵长类动物中进行的首次系统表型筛选和经典遗传图谱绘制，表明正向和反向遗传方法现在在狐猴中都是可行的。总体而言，这些进展有力地证明了小鼠狐猴是灵长类生物医学研究中一种有价值且实用的模式生物。
