MAZ mediates the cross-talk between CT-1 and NOTCH1 signaling during gliogenesis.

Bin Liu,Anyun Ma,Zengmin Li,Qingyu Li,Feng Zhang,Yumeng Wang,Zhiheng Xu,Yufang Zheng

doi:10.1038/srep21534

Abstract

Neurons and glia cells are differentiated from neural stem/progenitor cells (NSCs/NPCs) during brain development. Concomitant activation of JAK/STAT and NOTCH1 signaling is required for gliogenesis, a process to generate glia cells to ensure proper brain functions. NOTCH1 signaling is down-regulated during neurogenesis and up-regulated during gliogenesis. However, the underlying mechanism remains elusive. We report here that cardiotrophin-1 (CT-1) activates NOTCH1 signaling through the up-regulation of ADAM10, a rate-limiting factor of NOTCH1 signaling activation. We found that a transcriptional factor, Myc-associated zinc finger protein (MAZ), plays an important role in ADAM10 transcription in response to CT-1 in NPCs. MAZ knockdown inhibits CT-1 stimulated gliogenesis and it can be rescued by over-expressing human NICD. Our results provide a link between NOTCH1 activation and neuronal secreted CT-1, suggesting that CT-1 plays an important role in ensuring the coordinated activation of NOTCH1 signaling during gliogenesis.

Highlights

(NFIA)[16,19]
CT-1 induces the levels of ADAM10 and NICD in NPCs. Since both Notch and CT-1 signal pathways are involved in gliogenesis, we firstly investigated whether CT-1 has any effect on NOTCH1 pathway
Signal crosstalk between the NOTCH1 and CT-1/JAK/STAT pathways has been proposed to ensure a synchronized activation of both pathways for proper gliogenesis[16]

Summary

Introduction

It has been shown that NOTCH1 activates NFIA to release DNA (cytosine-5)-methyltransferase 1 (DNMT1) from the promoter of Glial fibrillary acidic protein (GFAP, a glia marker protein) during gliogenesis[5,9,20,21]. CT-1 stimulates gliogenesis by activating the JAK/STAT pathway and knockout of CT-1 in mouse brain causes the reduction of glia cells[24,25]. The expression of GFAP requires simultaneous activation of both NOTCH1 and JAK/STAT pathways as both CBF-1 and STAT3 bind to the promoter region of GFAP9. Both NOTCH1 and CT-1/JAK/STAT signals are essential for gliogenesis. Our results revealed a novel mechanism for the regulation of NOTCH1 signaling by CT-1 which is essential for gliogenesis

Methods

Results

Conclusion