Corrigendum: Mutation of Gemin5 causes defective hematopoietic stem/progenitor cells proliferation in zebrafish embryonic hematopoiesis.

[This corrects the article DOI: 10.3389/fcell.2021.670654.].

Mutation of Gemin5 Causes Defective Hematopoietic Stem/Progenitor Cells Proliferation in Zebrafish Embryonic Hematopoiesis.

Fate determination and expansion of Hematopoietic Stem and Progenitor Cells (HSPCs) is tightly regulated on both transcriptional and post-transcriptional level. Although transcriptional regulation of HSPCs have achieved a lot of advances, its post-transcriptional regulation remains largely underexplored. The small size and high fecundity of zebrafish makes it extraordinarily suitable to explore novel genes playing key roles in definitive hematopoiesis by large-scale forward genetics screening. Here, we reported a novel zebrafish mutant line gemin5 cas008 with a point mutation in gemin5 gene obtained by ENU mutagenesis and genetic screening, causing an earlier stop codon next to the fifth WD repeat. Gemin5 is an RNA-binding protein with multifunction in post-transcriptional regulation, such as regulating the biogenesis of snRNPs, alternative splicing, stress response, and translation control. The mutants displayed specific deficiency in definitive hematopoiesis without obvious defects during primitive hematopoiesis. Further analysis showed the impaired definitive hematopoiesis was due to defective proliferation of HSPCs. Overall, our results indicate that Gemin5 performs an essential role in regulating HSPCs proliferation.

Inhibition of PLCß1 signaling pathway regulates methamphetamine self-administration and neurotoxicity in rats.

Studies have shown that the central renin-angiotensin system is involved in neurological disorders. Our previous studies have demonstrated that angiotensin II receptor type 1 (AT1R) in the brain could be a potential target against methamphetamine (METH) use disorder. The present study was designed to investigate the underlying mechanisms of the inhibitory effect of AT1R on various behavioural effects of METH. We first examined the effect of AT1R antagonist, candesartan cilexetil (CAN), on behavioural and neurotoxic effects of METH. Furthermore, we studied the role of phospholipase C beta 1 (PLCß1) blockade behavioural and neurotoxic effects of METH. The results showed that CAN significantly attenuated METH-induced behavioral disorders and neurotoxicity associated with increased oxidative stress. AT1R and PLCß1 were significantly upregulated in vivo and in vitro. Inhibition of PLCß1 effectively alleviated METH-induced neurotoxicity and METH self-administration (SA) by central blockade of the PLCß1 involved signalling pathway. PLCß1 blockade significantly decreased the reinforcing and motivation effects of METH. PLCß1 involved signalling pathway, as well as a more specific role of PLCß1, involved the inhibitory effects of CAN on METH-induced behavioural dysfunction and neurotoxicity. Collectively, our findings reveal a novel role of PLCß1 in METH-induced neurotoxicity and METH use disorder.

Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition.

The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a (VEGFA) has been commonly recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in mice. In tumor models, CDS2 deficiency enhanced the level of tumor-secreted VEGFA, which in-turn trapped tumors into a VEGFA-induced vessel regression situation, leading to suppression of tumor growth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence of CDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression.