# TTBK2‐Driven Ciliogenesis Is Required for Intrinsic Neuronal Regeneration After Spinal Cord Injury

## TL;DR

TTBK2 helps neurons regenerate after spinal cord injury by supporting primary cilium function and SHH signaling.

## Contribution

This study reveals TTBK2-driven ciliogenesis as a novel endogenous repair mechanism for neuronal regeneration after SCI.

## Key findings

- Loss of TTBK2 disrupts primary cilium integrity and impairs axonal regrowth after spinal cord injury.
- Restoring SHH activity partially rescues neuronal structural deficits caused by TTBK2 deficiency.

## Abstract

The primary cilium (PC) is a pivotal organelle for neuronal signaling and development, while tau tubulin kinase 2 (TTBK2) is a key initiator of ciliogenesis. However, the role of TTBK2 in spinal neurons during spinal cord injury (SCI) and subsequent neural repair remains unclear.

We manipulated TTBK2 expression in spinal neurons using adenovirus‐mediated overexpression and knockdown in vitro. Transcriptomic profiling (RNA‐sequencing) and RT‐qPCR were employed to explore the potential regulatory pathways at the molecular level. In vivo, Ttbk2
fl/fl‐Rosa‐CreERT2+/− conditional knockout mice were subjected to a spinal cord hemisection model. Behavioral assays, immunofluorescence, and biotinylated dextran amine (BDA) tracing were conducted to assess neuronal survival, axonal regeneration, and circuit reorganization.

Here, we demonstrated that intact activity of TTBK2 in PC promoted neural survival, axonal regeneration, and neural circuit remodeling. However, loss of TTBK2 impaired PC function and hindered recovery after SCI.

These findings extend the role of PCs beyond neurodevelopment, demonstrating that the TTBK2–PC functions as an endogenous repair mechanism after SCI. Targeting this pathway may provide novel therapeutic strategies for enhancing neural regeneration.

TTBK2‐dependent ciliogenesis is required for intrinsic neuronal regeneration after spinal cord injury. Loss of TTBK2 disrupts primary cilium integrity, attenuates SHH signaling, and impairs axonal regrowth. Restoring SHH activity partially rescues neuronal structural deficits, highlighting the TTBK2/cilium–SHH as a therapeutic target.