Ubtor Mutation Causes Motor Hyperactivity by Activating mTOR Signaling in Zebrafish

Tiantian Wang,Quan Zhang,Gang Peng,Mingshan Zhou,Cuizhen Zhang

doi:10.1007/s12264-021-00755-z

Abstract

Mechanistic target of rapamycin (mTOR) signaling governs important physiological and pathological processes key to cellular life. Loss of mTOR negative regulators and subsequent over-activation of mTOR signaling are major causes underlying epileptic encephalopathy. Our previous studies showed that UBTOR/KIAA1024/MINAR1 acts as a negative regulator of mTOR signaling, but whether UBTOR plays a role in neurological diseases remains largely unknown. We therefore examined a zebrafish model and found that ubtor disruption caused increased spontaneous embryonic movement and neuronal activity in spinal interneurons, as well as the expected hyperactivation of mTOR signaling in early zebrafish embryos. In addition, mutant ubtor larvae showed increased sensitivity to the convulsant pentylenetetrazol, and both the motor activity and the neuronal activity were up-regulated. These phenotypic abnormalities in zebrafish embryos and larvae were rescued by treatment with the mTORC1 inhibitor rapamycin. Taken together, our findings show that ubtor regulates motor hyperactivity and epilepsy-like behaviors by elevating neuronal activity and activating mTOR signaling.

Highlights

Mechanistic target of rapamycin is an evolutionarily conserved serine-threonine protein kinase
We performed in situ hybridization (ISH) analysis of 28-hpf zebrafish embryos and found that ubtor mRNA was enriched in the spinal cord and hindbrain, with little to no signal detected in other structures (Fig. 1A)
We showed that the spontaneous movements of ubtor mutant zebrafish were increased compared with the wild-type control group, and neuronal activity in the ubtor mutant was elevated

Summary

Introduction

Mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine-threonine protein kinase. To determine whether the hyperactive phenotypic features of ubtor mutant larvae were correlated with increased neuronal activity, we assessed the expression of the c-fos gene in the spinal cord neurons of 28-hpf embryos.

Results

Conclusion