Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation.

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Tác giả: Gary J Brouhard, Adam G Hendricks, Alexandra L Paquette, Emily N P Prowse, Muriel Sébastien

Ngôn ngữ: eng

Ký hiệu phân loại: 519.234 Branching processes

Thông tin xuất bản: England : Nature communications , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 203942

Doublecortin is a neuronal microtubule-associated protein that regulates microtubule structure in neurons. Mutations in Doublecortin cause lissencephaly and subcortical band heterotopia by impairing neuronal migration. We use CRISPR/Cas9 to knock-out the Doublecortin gene in induced pluripotent stem cells and differentiate the cells into cortical neurons. DCX-KO neurons show reduced velocities of nuclear movements and an increased number of neurites early in neuronal development, consistent with previous findings. Neurite branching is regulated by a host of microtubule-associated proteins, as well as by microtubule polymerization dynamics. However, EB comet dynamics are unchanged in DCX-KO neurons. Rather, we observe a significant reduction in α-tubulin polyglutamylation in DCX-KO neurons. Polyglutamylation levels and neuronal branching are rescued by expression of Doublecortin or of TTLL11, an α-tubulin glutamylase. Using U2OS cells as an orthogonal model system, we show that DCX and TTLL11 act synergistically to promote polyglutamylation. We propose that Doublecortin acts as a positive regulator of α-tubulin polyglutamylation and restricts neurite branching. Our results indicate an unexpected role for Doublecortin in the homeostasis of the tubulin code.
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