Bracha Teva W, Luong Nina, Leffler Joseph, Sivyer Benjamin, Wright Kevin M
Neuroscience Graduate Program, Oregon Health & Science University, Portland, Oregon 97239.
Casey Eye Institute, Oregon Health & Science University, Portland, Oregon 97239.
bioRxiv. 2025 May 8:2025.05.08.652956. doi: 10.1101/2025.05.08.652956.
Neurons are subject to extensive developmental regulation to ensure precise subtype-specific morphologies that are intimately tied to their function. Starburst amacrine cells (SACs) in the mammalian retina have a highly stereotyped, radially symmetric dendritic arbor that is essential for their role in direction-selective circuits in the retina. We show that PTEN, the primary negative regulator of the PI3K-AKT-mTOR pathway that is highly implicated in neurodevelopmental disorders, regulates SAC morphology in a cell-autonomous manner. -deficient SACs show a nearly twofold increase in the number of dendritic branches, while other morphological properties remain largely unchanged. These morphological changes arise late in SAC development after dendrite development is largely complete and persist into adulthood. Mechanistically, excessive dendritic branching appears to arise from dysregulated mTOR activity. Despite this dramatic increase in dendritic branches, -deficient SACs maintain a normal population number, organization of synaptic outputs, and intact direction-selectivity in the retina. Collectively, these results show that PTEN is essential for the normal development of highly stereotyped neuronal morphology.
神经元受到广泛的发育调控，以确保形成与功能紧密相关的精确的亚型特异性形态。哺乳动物视网膜中的星爆无长突细胞（SACs）具有高度定型的、径向对称的树突分支，这对于它们在视网膜方向选择性回路中的作用至关重要。我们发现，PTEN是PI3K-AKT-mTOR通路的主要负调控因子，与神经发育障碍高度相关，它以细胞自主方式调节SAC形态。PTEN缺陷的SACs树突分支数量增加近两倍，而其他形态学特性基本保持不变。这些形态学变化出现在SAC发育后期，此时树突发育基本完成，并持续到成年期。从机制上讲，过度的树突分支似乎源于mTOR活性失调。尽管树突分支显著增加，但PTEN缺陷的SACs在视网膜中保持正常的细胞数量、突触输出组织和完整的方向选择性。总的来说，这些结果表明PTEN对于高度定型的神经元形态的正常发育至关重要。
