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Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration

ABSTRACT: Tetratricopeptide repeat domain 5 (TTC5) mediates the co-translational degradation of tubulin transcripts in response to excess soluble tubulin, a.k.a. “tubulin autoregulation”. TTC5 mutations associate with cerebral atrophy, speech and motor impairment; however, the role of TTC5 and tubulin autoregulation in neuronal development are unknown. Using a human iPSC-derived cortical-like neuron model, we show that tubulin autoregulation is activated during neuronal differentiation and is TTC5-dependent. Across differentiation, TTC5 loss suppresses microtubule polymerization and impairs axonal outgrowth and arborization. Moreover, TTC5 loss, or CRISPR knock-in of either an autoregulation-defective point mutant or previously uncharacterized patient disease mutants, unexpectedly stimulate neuronal motility. These phenotypes recapitulate in vivo where TTC5 loss in mouse cerebral cortex projection neurons (CPNs) alters axon arborization and promotes aberrant hypermigration. Our work is the first characterization of autoregulation and its mediators in neurons, and the first to reveal the functional impact of TTC5 disease mutations and connect them to clinically relevant phenotypes both in a human and mouse system. This RNA-Seq dataset was part of comprehensively characterizing the transcriptomic response to colchicine treatment in WT and TTC5 knock-down D14 i3Neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312628 | GEO | 2026/09/23

REPOSITORIES: GEO

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Project description:To guarantee blood supply throughout adult life hematopoietic stem cells (HSCs) need to carefully balance between self-renewing cell divisions and quiescence. Identification of genes controlling HSC self-renewal is of utmost importance given that HSCs are the only stem cells with broad clinical applications. Transcription factor PU.1 is one of the major regulators of myeloid and lymphoid development. Recent reports suggest that PU.1 mediates its functions via gradual expression level changes rather than binary on/off states. So far, this has not been considered in any study of HSCs and thus, PU.1’s role in HSC function has remained largely unclear. Here we demonstrate using hypomorphic mice with an engineered disruption of an autoregulatory feedback loop that decreased PU.1 levels resulted in loss of key HSC functions, all of which could be fully rescued by restoration of proper PU.1 levels via a human PU.1 transgene. Mechanistically, we found excessive HSC cell divisions and altered expression of cell cycle regulators whose promoter regions were bound by PU.1 in normal HSCs. Adequate PU.1 levels were maintained by a mechanism of direct autoregulation restricted to HSCs through a physical interaction of a -14kb enhancer with the proximal promoter. Our findings identify PU.1 as novel regulator controling the switch between cell division and quiescence in order to prevent exhaustion of HSCs. Given that even moderate level changes greatly impact stem cell function, our data suggest important therapeutic implications for leukemic patients with reduced PU.1 levels. Moreover, we provide first proof, that autoregulation of a transcription factor, PU.1, has a crucial function in vivo. We anticipate that our concept of how autoregulation forms an active chromosomal conformation will impact future research on transcription factor networks regulating stem cell fate. HSCs of Pu.1 knock-in (PU.1ki/ki) mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the corresponding wild type.

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Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration

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