Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells–derived neural rosettes

Abstract

Primary cilia are key regulators of embryo development and tissue homeostasis. However, their mechanisms and functions, particularly in the context of human cells, are still unclear. Here, we analyzed the consequences of primary cilia modulation for human pluripotent stem cells (hPSCs) proliferation and differentiation. We show that neither activation of the cilia-associated Hedgehog signaling pathway nor ablation of primary cilia by CRISPR gene editing to knockout Tau Tubulin Kinase 2 (TTBK2), a crucial ciliogenesis regulator, affects the self-renewal of hPSCs. In addition, we demonstrate that TTBK1, a closely related kinase without previous links to ciliogenesis, is upregulated during hPSCs-derived neural rosette differentiation to regulate primary cilia formation together with TTBK2. Finally, we show that TTBK1/2 and primary cilia are implicated in the regulation of the size of hPSCs-derived neural rosettes.

Tau-Tubulin Kinase 2 restrains microtubule-depolymerizer KIF2A to support primary cilia growth

“…Furthermore, we speculate that concentrated TTBK2 activity at the MC is not strictly necessary for the phosphorylation of at least some of its basal body substrates, provided the levels and activity of the kinase outside of the MC are sufficiently high. In fact, our recent work has demonstrated that TTBK1, which does not localize to the MC, is able to partially support cilia formation in TTBK2 KO 42 , in line with the activities of TTBK2 trunc1/2 reported here.…”