Whole Genome and Embryo Transcriptome Analysis of Vertebrate IdentifiesnxhlControlling Angiogenesis by Targeting VE-PTP
Authors: Luo Honglin , Zhang Yongde , Ji Changmian , Zhao Yongzhen , Peng Jinxia , Chen Xiuli , Huang Yin , Liu Qingyun , He Pingping , Feng Pengfei , Yang Chunling , Wei Pinyuan , Yu Haiyan , Zheng Hongkun , Lin Yong , Chen Xiaohan 
Published: October 2019

BACKGROUND

Angiogenesis is closely associated with angiogenesis-dependent diseases including cancers and ocular diseases. Anti-angiogenic therapeutics have been focusing on the (VEGF)/VEGFR signaling axis. However, the clinical resistance, high cost and frequent administration of anti-VEGF drugs make it urgent to discover novel angiogenic pathways.VE-PTP (ptprb) is a novel target with great anti-angiogenic potential. However, it is unclear whether upstream signaling pathways targeting VE-PTP exist in angiogenesis.

METHODS

Whole genome and embryo transcriptome sequencing were applied to discover the new genenxhl. Transgenic zebrafish model, morpholino knockdown and small interfering RNA were used to explore the role ofnxhlin angiogenesis bothin vitroandin vivo. RNA pulldown, RIP and ChIRP-MS were used to identify interactions between RNA and protein.

RESULTS

We discovered a novel zebrafish genenxhlwhich is a homologue of the conserved genenxhthat co-expressed with some key genes essential for embryo development in vertebrate.Nxhldeletion causes angiogenesis defects in embryo. Moreover,nxhlis essential to mediate effects of angiogenesisin vivoandin vitro, andptprbdepletion duplicates the phenotypes ofnxhldeficiency. Importantly,nxhlacts upstream ofptprband regulates many extreme importantptprb-linked angiogenic genes by targeting VE-PTP (ptprb) through interactions with NCL. Notably,nxhldeletion decreases the phosphorylation of NCL T76 and increases the acetylation of NCL K88, suggestingnxhlmay regulate downstream VE-PTP signaling pathways by mediation of NCL posttranslational modification. This is the first description of the interaction betweennxhland NCL, NCL and VE-PTP (ptprb), uncovering a novelnxhl-NCL-VE-PTP signaling pathway on angiogenesis regulation.

CONCLUSIONS

Our study identifiesnxhlcontrolling angiogenesis by targeting VE-PTP through interactions with NCL, uncovering novel upstream controllers of VE-PTP. Thisnxhl-NCL-VE-PTP pathway may be a therapeutic target in the treatment of angiogenesis-dependent diseases.

Clinical Perspective

What Is New?

We report a novelnxhl-NCL-VE-PTP signaling pathway that controls angiogenesis.

We for the first time demonstrate thatnxhlinteracts with NCL which simultaneously binds to VE-PTP that plays key roles on EC adherens junction, integrity and vascular homeostasis.

Nxhlalso controls some other crucial VE-PTP-linked downstream angiogenic genes (such as Tie2, VEGFaa, VEGFR2, Erbb2, S1pr1 and Hey2) which explain the phenotypes induced by thenxhldeficiency.

Our study indicates the key role ofnxhlon controlling angiogenesis as an upstream regulator of VE-PTP.

What Are the Clinical Implications?

There are several ongoing researches investigating the utility of VE-PTP or NCL inhibitors on treatment of angiogenesis-dependent diseases including a range of cancers and nonneoplastic diseases, such as AMD, DME, RA and atherosclerosis.

Targeting thenxhl-NCL-VE-PTP pathway may facilitate therapeutic angiogenesis in patients with cancers or ocular diseases such as DME.

Our study highlights the great potential ofnxhlon anti-angiogenic therapeutics by targeting VE-PTP.