The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure.

Expression levels and stoichiometry of Hnf1β, Emx2, Pax8 and Hnf4 influence direct reprogramming of induced renal tubular epithelial cells.

Generation of induced renal epithelial cells (iRECs) from fibroblasts offers great opportunities for renal disease modeling and kidney regeneration. However, the low reprogramming efficiency of the current approach to generate iRECs has hindered potential therapeutic application and regenerative approach. This could be in part attributed to heterogeneous and unbalanced expression of reprogramming factors (RFs) Hnf1β (H1), Emx2 (E), Pax8 (P), and Hnf4α (H4) in transduced fibroblasts.

Renal interstitial cells promote nephron regeneration by secreting prostaglandin E2.

In organ regeneration, progenitor and stem cells reside in their native microenvironment, which provides dynamic physical and chemical cues essential to their survival, proliferation, and differentiation. However, the types of cells that form the native microenvironment for renal progenitor cells (RPCs) have not been clarified. Here, single-cell sequencing of zebrafish kidney reveals as a principal marker of renal interstitial cells (RICs), which can be specifically labeled by GFP under the control of promoter in the transgenic zebrafish.

Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.

Hematopoietic stem and progenitor cells (HSPCs) are a heterogeneous group of cells with expansion, differentiation, and repopulation capacities. How HSPCs orchestrate the stemness state with diverse lineage differentiation at steady condition or acute stress remains largely unknown. Here, we show that zebrafish mutants that are deficient in an epigenetic regulator Atf7ip or Setdb1 methyltransferase undergo excessive myeloid differentiation with impaired HSPC expansion, manifesting a decline in T cells and erythroid lineage.

Requirement of Zebrafish Adcy3a and Adcy5 in Melanosome Dispersion and Melanocyte Stripe Formation.

cAMP-PKA signaling plays a pivotal role in melanin synthesis and melanosome transport by responding to the binding of the α-melanocyte-stimulating hormone (α-MSH) to melanocortin-1 receptor (MC1R). Adenylate cyclases (ADCYs) are the enzymes responsible for the synthesis of cAMP from ATP, which comprises nine transmembrane isoforms (ADCYs 1-9) and one soluble adenylate cyclase (ADCY 10) in mammals. However, little is known about which and how ADCY isoforms regulate melanocyte generation, melanin biosynthesis, and melanosome transport in vivo.

Wnt Signaling in Heart Development and Regeneration.

Purpose Of Review: Cardiovascular diseases are the leading cause of death worldwide, largely due to the limited regenerative capacity of the adult human heart. In contrast, teleost zebrafish hearts possess natural regeneration capacity by proliferation of pre-existing cardiomyocytes after injury. Hearts of mice can regenerate if injured in a few days after birth, which coincides with the transient capacity for cardiomyocyte proliferation.

PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis.

Prostaglandin E2 (PGE2), a major cyclooxygenase-2 (COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis (OA) patients. However, NSAIDs, including COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of PGE2 signaling in OA progression is urgently needed.

A novel prostaglandin E receptor 4 (EP4) small molecule antagonist induces articular cartilage regeneration.

Articular cartilage repair and regeneration is an unmet clinical need because of the poor self-regeneration capacity of the tissue. In this study, we found that the expression of prostaglandin E receptor 4 (PTGER4 or EP4) was largely increased in the injured articular cartilage in both humans and mice. In microfracture (MF) surgery-induced cartilage defect (CD) and destabilization of the medial meniscus (DMM) surgery-induced CD mouse models, cartilage-specific deletion of EP4 remarkably promoted tissue regeneration by enhancing chondrogenesis and cartilage anabolism, and suppressing cartilage catabolism and hypertrophy.

Prostaglandin signaling in ciliogenesis and development.

Prostaglandin (PG) signaling regulates a wide variety of physiological and pathological processes, including body temperature, cardiovascular homeostasis, reproduction, and inflammation. Recent studies have revealed that PGs play pivotal roles in embryo development, ciliogenesis, and organ formation. Prostaglandin E2 (PGE2) and its receptor EP4 modulate ciliogenesis by increasing the anterograde intraflagellar transport.

The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy.

Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT.

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway.

Gene alterations are recognized as important events in acute myeloid leukemia (AML) progression. Studies on hematopoiesis of altered genes contribute to a better understanding on their roles in AML progression. Our previous work reported a DEAH box helicase 15 (DHX15) R222G mutation in AML patients, and we showed DHX15 overexpression is associated with poor prognosis in AML patients.

Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration.

Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites.

Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis.

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available.

The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase.

Teleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in (; also known as ), encoding a Hairy-related basic helix-loop-helix transcriptional repressor, enhance CM proliferation and reduce fibrosis following damage.

Tbx20 Induction Promotes Zebrafish Heart Regeneration by Inducing Cardiomyocyte Dedifferentiation and Endocardial Expansion.

Heart regeneration requires replenishment of lost cardiomyocytes (CMs) and cells of the endocardial lining. However, the signaling regulation and transcriptional control of myocardial dedifferentiation and endocardial activation are incompletely understood during cardiac regeneration. Here, we report that T-Box Transcription Factor 20 (Tbx20) is induced rapidly in the myocardial wound edge in response to various sources of cardiac damages in zebrafish.

Systematic genome editing of the genes on zebrafish Chromosome 1 by CRISPR/Cas9.

Genome editing by the well-established CRISPR/Cas9 technology has greatly facilitated our understanding of many biological processes. However, a complete whole-genome knockout for any species or model organism has rarely been achieved. Here, we performed a systematic knockout of all the genes (1333) on Chromosome 1 in zebrafish, successfully mutated 1029 genes, and generated 1039 germline-transmissible alleles corresponding to 636 genes.

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.

Tubgcp3 Is Required for Retinal Progenitor Cell Proliferation During Zebrafish Development.

The centrosomal protein γ-tubulin complex protein 3 (Tubgcp3/GCP3) is required for the assembly of γ-tubulin small complexes (γ-TuSCs) and γ-tubulin ring complexes (γ-TuRCs), which play critical roles in mitotic spindle formation during mitosis. However, its function in vertebrate embryonic development is unknown. Here, we generated the zebrafish mutants using the CRISPR/Cas9 system and found that the mutants exhibited the small eye phenotype.

Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair.

There are intense interests in discovering proregenerative medicine leads that can promote cardiac differentiation and regeneration, as well as repair damaged heart tissues. We have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse effects. Two related compounds with novel structures, named as Cardiomogen 1 and 2 (CDMG1 and CDMG2), were identified for their capacity to promote myocardial hyperplasia through expansion of the cardiac progenitor cell population.

Photoreceptor cell development requires prostaglandin signaling in the zebrafish retina.

Photoreceptor cells are highly specialized sensory neurons capable of visual phototransduction. The connecting cilia in the retinal photoreceptors link the inner segment to the outer segment and mediate the transport of opsins in vision. Although our previous study demonstrates that Prostaglandin E2 (PGE) signaling is required for ciliogenesis in zebrafish, its roles in retinal ciliogenesis and photoreceptor cell development remain unknown.

Report of the Fifth Zebrafish Research Conference of China.

The fifth zebrafish research conference of China was held from October 29 to November 1, 2017, at Wuzhen, China, a beautiful small town that is close to Shanghai. The organizing committee, composed of Tao P. Zhong, Ruilin Zhang, Jie He, Xu Wang, Weijun Pan, Ying Cao, Yao Zu, Qiu Jiang, and Jiulin Du, organized enthusiastically and successfully the 4-day meeting.