Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida; Doctoral Program in Chemical and Biological Sciences, The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, Florida.
Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida; The Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, Florida.
Biol Psychiatry. 2021 Sep 1;90(5):295-306. doi: 10.1016/j.biopsych.2021.01.012. Epub 2021 Apr 8.
Mutations in DYRK1A are a cause of microcephaly, autism spectrum disorder, and intellectual disability; however, the underlying cellular and molecular mechanisms are not well understood.
We generated a conditional mouse model using Emx1-cre, including conditional heterozygous and homozygous knockouts, to investigate the necessity of Dyrk1a in the cortex during development. We used unbiased, high-throughput phosphoproteomics to identify dysregulated signaling mechanisms in the developing Dyrk1a mutant cortex as well as classic genetic modifier approaches and pharmacological therapeutic intervention to rescue microcephaly and neuronal undergrowth caused by Dyrk1a mutations.
We found that cortical deletion of Dyrk1a in mice causes decreased brain mass and neuronal size, structural hypoconnectivity, and autism-relevant behaviors. Using phosphoproteomic screening, we identified growth-associated signaling cascades dysregulated upon Dyrk1a deletion, including TrkB-BDNF (tyrosine receptor kinase B-brain-derived neurotrophic factor), an important regulator of ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) and mTOR (mammalian target of rapamycin) signaling. Genetic suppression of Pten or pharmacological treatment with IGF-1 (insulin-like growth factor-1), both of which impinge on these signaling cascades, rescued microcephaly and neuronal undergrowth in neonatal mutants.
Altogether, these findings identify a previously unknown mechanism through which Dyrk1a mutations disrupt growth factor signaling in the developing brain, thus influencing neuronal growth and connectivity. Our results place DYRK1A as a critical regulator of a biological pathway known to be dysregulated in humans with autism spectrum disorder and intellectual disability. In addition, these data position Dyrk1a within a larger group of autism spectrum disorder/intellectual disability risk genes that impinge on growth-associated signaling cascades to regulate brain size and connectivity, suggesting a point of convergence for multiple autism etiologies.
DYRK1A 基因突变是小头畸形、自闭症谱系障碍和智力障碍的一个原因；然而，其潜在的细胞和分子机制尚不清楚。
我们使用 Emx1-cre 生成了一种条件性小鼠模型，包括条件性杂合和纯合敲除，以研究 Dyrk1a 在发育过程中对皮层的必要性。我们使用无偏的高通量磷酸蛋白质组学来鉴定发育中的 Dyrk1a 突变体皮层中失调的信号机制，以及经典的遗传修饰方法和药物治疗干预，以挽救 Dyrk1a 突变引起的小头畸形和神经元生长不良。
我们发现，在小鼠中皮层缺失 Dyrk1a 会导致脑质量和神经元大小减小、结构连接减少以及自闭症相关行为。通过磷酸蛋白质组学筛选，我们发现 Dyrk1a 缺失后，与生长相关的信号级联被失调，包括 TrkB-BDNF（酪氨酸受体激酶 B-脑源性神经营养因子），这是 ERK/MAPK（细胞外信号调节激酶/丝裂原活化蛋白激酶）和 mTOR（哺乳动物雷帕霉素靶蛋白）信号的重要调节剂。Pten 的遗传抑制或 IGF-1（胰岛素样生长因子-1）的药物治疗，都可以抑制这些信号级联，从而挽救新生突变体的小头畸形和神经元生长不良。
总之，这些发现确定了一个以前未知的机制，通过该机制，Dyrk1a 突变破坏了发育中的大脑中生长因子信号，从而影响神经元的生长和连接。我们的结果将 DYRK1A 确定为一个关键调节因子，该因子在自闭症谱系障碍和智力障碍患者中失调的生物学途径中发挥作用。此外，这些数据将 Dyrk1a 置于一个更大的自闭症谱系障碍/智力障碍风险基因组中，这些基因通过影响与生长相关的信号级联来调节大脑大小和连接，表明了多种自闭症病因的一个汇聚点。
