The neurodevelopmental transcriptome of the Drosophila melanogaster microcephaly gene abnormal spindle reveals a role for temporal transcription factors and the immune system in regulating brain size.
The neurodevelopmental transcriptome of the Drosophila melanogaster microcephaly gene abnormal spindle reveals a role for temporal transcription factors and the immune system in regulating brain size.
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果蝇小头畸形基因异常纺锤体的神经发育转录组揭示了时间转录因子和免疫系统在调节大脑大小中的作用。
DOI：
10.1101/2023.01.09.523369
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Schoborg,Todd
中科院分区：
文献类型：
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作者：
Mannino,MariaC;BartelsCassidy,Mercedes;Florez,Steven;Rusan,Zeid;Chakraborty,Shalini;Schoborg,Todd
神经发育过程中细胞行为的协调对于决定中枢神经系统的形式、功能和大小至关重要。脊椎动物异常纺锤体样小头畸形相关(ASPM)基因及其与黑腹果蝇同源的纺锤体异常(Asp)基因突变导致小头畸形，小头畸形的病因尚不清楚。在这里，我们提供了常染色体隐性原发小头畸形(MCPH)果蝇模型的神经发育转录图谱，并将我们的发现扩展到功能领域，试图确定负责天冬氨酸依赖的脑生长和发育的关键细胞机制。我们确定了多个转录转录特征，包括在发育中的中枢神经系统中共表达基因的新模式。在幼虫大脑中，通过下调时间转录因子(TTF)和Notch信号靶标，发现了视叶神经发生的缺陷，这与在神经发生发育窗口期间大脑大小和细胞总数的显著减少有关。我们还发现炎症是asp MCPH脑的一个标志，在中枢神经系统发育的每个阶段都可以检测到，这也与脑大小表型有关。最后，我们表明细胞凋亡不是asp MCPH表型的主要驱动因素，进一步强调了一种内在的Asp依赖的神经发生促进机制，该机制独立于细胞死亡。总而言之，我们的结果表明，asp mcph的病因是复杂的，对这种疾病的细胞基础的全面看法需要了解多个途径的输入如何共同决定小头畸形的表型。
The coordination of cellular behaviors during neurodevelopment is critical for determining the form, function, and size of the central nervous system. Mutations in the vertebrate Abnormal Spindle-Like, Microcephaly Associated (ASPM) gene and its Drosophila melanogaster ortholog abnormal spindle (asp) lead to microcephaly, a reduction in overall brain size whose etiology remains poorly defined. Here we provide the neurodevelopmental transcriptional landscape for a Drosophila model for autosomal recessive primary microcephaly (MCPH) and extend our findings into the functional realm in an attempt to identify the key cellular mechanisms responsible for Asp-dependent brain growth and development. We identify multiple transcriptomic signatures, including new patterns of co-expressed genes in the developing CNS. Defects in optic lobe neurogenesis were detected in larval brains through downregulation of temporal transcription factors (tTFs) and Notch signaling targets, which correlated with a significant reduction in brain size and total cell numbers during the neurogenic window of development. We also found inflammation as a hallmark of asp MCPH brains, detectable throughout every stage of CNS development, which also contributes to the brain size phenotype. Finally, we show that apoptosis is not a primary driver of the asp MCPH phenotype, further highlighting an intrinsic Asp-dependent neurogenesis promotion mechanism that is independent of cell death. Collectively, our results suggest that the etiology of asp MCPH is complex and that a comprehensive view of the cellular basis of the disorder requires an understanding of how multiple pathway inputs collectively determine the microcephaly phenotype.