Mea6/cTAGE5 cooperates with TRAPPC12 to regulate PTN secretion and white matter development

Tiantian Ma; Yaqing Wang; Laikang Yu; Jinghua Liu; Tao Wang; Pengyu Sun; Yinghang Feng; Dan Zhang; Lei Shi; Kangmin He; Li Zhao; Zhiheng Xu

doi:10.1016/j.isci.2024.109180

Mea6/cTAGE5 cooperates with TRAPPC12 to regulate PTN secretion and white matter development

iScience. 2024 Feb 8;27(3):109180. doi: 10.1016/j.isci.2024.109180. eCollection 2024 Mar 15.

Authors

Tiantian Ma^{1

2}, Yaqing Wang^{1

2}, Laikang Yu³, Jinghua Liu^{1

2}, Tao Wang¹, Pengyu Sun^{1

2}, Yinghang Feng^{1

2}, Dan Zhang^{1

2}, Lei Shi¹, Kangmin He^{1

2}, Li Zhao³, Zhiheng Xu^{1

2}

Affiliations

¹ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
² University of Chinese Academy of Sciences, Beijing 100083, China.
³ Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing, Haidian District, China.

Abstract

Mutations of TRAPPC12 are associated with progressive childhood encephalopathy including abnormal white matter. However, the underlying pathogenesis is still unclear. Here, we found that Trappc12 deficiency in CG4 and oligodendrocyte progenitor cells (OPCs) affects their differentiation and maturation. In addition, TRAPPC12 interacts with Mea6/cTAGE5, and Mea6/cTAGE5 ablation in OPCs affects their proliferation and differentiation, leading to marked hypomyelination, compromised synaptic functionality, and aberrant behaviors in mice. We reveal that TRAPPC12 is associated with COPII components at ER exit site, and Mea6/cTAGE5 cKO disrupts the trafficking pathway by affecting the distribution and/or expression of TRAPPC12, SEC13, SEC31A, and SAR1. Moreover, we observed marked disturbances in the secretion of pleiotrophin (PTN) in Mea6-deficient OPCs. Notably, exogenous PTN supplementation ameliorated the differentiation deficits of these OPCs. Collectively, our findings indicate that the association between TRAPPC12 and MEA6 is important for cargo trafficking and white matter development.

Keywords: Developmental neuroscience; Molecular biology.