scholarly journals Prostaglandin signaling regulates nephron segment patterning of renal progenitors during zebrafish kidney development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Shahram Jevin Poureetezadi ◽  
Christina N Cheng ◽  
Joseph M Chambers ◽  
Bridgette E Drummond ◽  
Rebecca A Wingert
Keyword(s):  
Birth Defects ◽  
Kidney Development ◽  
Distal Segment ◽  
Genetic Screen ◽  
Prostaglandin Synthesis ◽  
Lipid Mediators ◽  
Chemical Genetic ◽  
Nephron Segment ◽  
Renal Progenitors ◽  
First Time

Kidney formation involves patterning events that induce renal progenitors to form nephrons with an intricate composition of multiple segments. Here, we performed a chemical genetic screen using zebrafish and discovered that prostaglandins, lipid mediators involved in many physiological functions, influenced pronephros segmentation. Modulating levels of prostaglandin E2 (PGE2) or PGB2 restricted distal segment formation and expanded a proximal segment lineage. Perturbation of prostaglandin synthesis by manipulating Cox1 or Cox2 activity altered distal segment formation and was rescued by exogenous PGE2. Disruption of the PGE2 receptors Ptger2a and Ptger4a similarly affected the distal segments. Further, changes in Cox activity or PGE2 levels affected expression of the transcription factors irx3b and sim1a that mitigate pronephros segment patterning. These findings show for the first time that PGE2 is a regulator of nephron formation in the zebrafish embryonic kidney, thus revealing that prostaglandin signaling may have implications for renal birth defects and other diseases.

scholarly journals Tfap2a is a novel gatekeeper of differentiation in renal progenitors during kidney development

2018 ◽  
Author(s):  
Brooke E. Chambers ◽  
Gary F. Gerlach ◽  
Karen H. Chen ◽  
Eleanor G. Clark ◽  
Ignaty Leshchiner ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Genetic Control ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Kidney Development ◽  
Distal Segment ◽  
Distal Nephron ◽  
Nephron Segment ◽  
Gene Regulatory ◽  
First Time

AbstractRenal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular populations with discrete physiological tasks. Knowledge about the terminal differentiation programs of each nephron segment has central importance for understanding kidney disease and to advance regenerative medicine, as mammalian nephrons grown in organoid cultures from pluripotent cells fail to terminally differentiate. Here, from a novel forward genetic screen using zebrafish we report the discovery that transcription factor AP-2 alpha (tfap2a) coordinates a gene regulatory network that controls the progression of nephron distal segment progenitors into the differentiated state. Overexpression of tfap2a rescued differentiation in mutants and caused ectopic expression of distal segment markers in wild-type nephrons, indicating tfap2a is sufficient to instigate the distal segment differentiation program. tfap2a/2b deficiency exacerbated distal nephron segment differentiation defects, revealing functional redundancy where tfap2a has a dominant role upstream of its family member. With further genetic studies, we assembled a blueprint of the tfap2a gene regulatory network during nephrogenesis. We demonstrate that tfap2a acts downstream of Iroquois homeobox 3b, a conserved distal lineage transcription factor. tfap2a controls a circuit consisting of irx1a, tfap2b, and genes encoding solute transporters that dictate the specialized metabolic functions of the distal nephron segments, and we show for the first time that this regulatory node is distinct from the pathway circuits controlling aspects such as apical-basal polarity and ciliogenesis during the differentiation process. Thus, our studies reveal new insights into the genetic control of differentiation, where tfap2a regulates the suite of segment transporter traits. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesis in vivo to make functional units that can facilitate organoid applications such as drug discovery and regenerative therapies.Summary StatementHere, we report for the first time that transcription factor AP-2 alpha (tfap2a) controls the progression from nephron progenitor into the fully differentiated state. This fundamentally deepens our knowledge about the genetic control of kidney development.

scholarly journals Kctd15 regulates nephron segment development by repressing Tfap2a activity

2020 ◽  
Author(s):  
Brooke E. Chambers ◽  
Eleanor G. Clark ◽  
Allison E. Gatz ◽  
Rebecca A. Wingert
Keyword(s):  
Transcription Factor ◽  
Kidney Development ◽  
Distal Tubule ◽  
Thick Ascending Limb ◽  
Nephron Progenitors ◽  
Nephron Segment ◽  
Feedback Module ◽  
Zebrafish Pronephros ◽  
First Time ◽  
Solute Transporters

AbstractA functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules that contain a sequence of segments each expressing a distinct repertoire of solute transporters. To date, the transcriptional codes driving regional specification, solute transporter program activation, and terminal differentiation of segment populations remain poorly understood. We demonstrate for the first time that the KCTD15 paralogs, kctd15a and kctd15b, function in concert to restrict distal early (DE)/thick ascending limb (TAL) segment lineage assignment in the developing zebrafish pronephros by repressing Tfap2a activity. During renal ontogeny, expression of these factors co-localized with tfap2a in distal tubule precursors. kctd15 loss primed nephron cells to adopt distal fates by driving expansions in slc12a1, kcnj1a.1, and stc1 marker expression. These phenotypes were resultant of Tfap2a hyperactivity, where kctd15a/b-deficient embryos exhibited increased abundance of this transcription factor. Interestingly, tfap2a reciprocally promoted kctd15 transcription, unveiling a circuit of autoregulation operating in nephron progenitors. Concomitant kctd15b knockdown with tfap2a overexpression produced genetic synergy and further expanded the DE population. Our study provides strong evidence that a transcription factor-repressor feedback module employs tight regulation of Tfap2a and Kctd15 kinetics to control nephron segment fate choice and differentiation during kidney development.

scholarly journals Author response: Prostaglandin signaling regulates nephron segment patterning of renal progenitors during zebrafish kidney development

2016 ◽  
Author(s):  
Shahram Jevin Poureetezadi ◽  
Christina N Cheng ◽  
Joseph M Chambers ◽  
Bridgette E Drummond ◽  
Rebecca A Wingert
Keyword(s):  
Kidney Development ◽  
Author Response ◽  
Nephron Segment ◽  
Renal Progenitors

Forward chemical genetic screen for oxygen‐dependent cytotoxins uncovers new covalent fragments that target GPX4

ChemBioChem ◽  
2021 ◽  
Author(s):  
Marie Cordon ◽  
Kristian Jacobsen ◽  
Cecilie Nielsen ◽  
Per Hjerrild ◽  
Thomas Bjørnskov Poulsen
Keyword(s):  
Genetic Screen ◽  
Chemical Genetic

scholarly journals Nicotinic acid promotes sleep through prostaglandin synthesis in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Éva Szentirmai ◽  
Levente Kapás
Keyword(s):  
Body Temperature ◽  
Nicotinic Acid ◽  
Prostaglandin Synthesis ◽  
Systemic Administration ◽  
Regulatory Mechanisms ◽  
Cyclooxygenase Inhibitor ◽  
Rapid Eye Movement Sleep ◽  
Oral Gavage ◽  
Monomethyl Fumarate ◽  
First Time

AbstractNicotinic acid has been used for decades for its antiatherogenic properties in humans. Its actions on lipid metabolism intersect with multiple sleep regulatory mechanisms, but its effects on sleep have never been documented. For the first time, we investigated the effects of acute systemic administration of nicotinic acid on sleep in mice. Intraperitoneal and oral gavage administration of nicotinic acid elicited robust increases in non-rapid-eye movement sleep (NREMS) and decreases in body temperature, energy expenditure and food intake. Preventing hypothermia did not affect its sleep-inducing actions suggesting that altered sleep is not secondary to decreased body temperature. Systemic administration of nicotinamide, a conversion product of nicotinic acid, did not affect sleep amounts and body temperature, indicating that it is not nicotinamide that underlies these actions. Systemic administration of monomethyl fumarate, another agonist of the nicotinic acid receptor GPR109A, fully recapitulated the somnogenic and thermoregulatory effects of nicotinic acid suggesting that they are mediated by the GPR109A receptor. The cyclooxygenase inhibitor indomethacin completely abolished the effects of nicotinic acid indicating that prostaglandins play a key role in mediating the sleep and thermoregulatory responses of nicotinic acid.

scholarly journals Novel insights into the mechanisms of pregnancy establishment: regulation of prostaglandin synthesis and signaling in the pig

Reproduction ◽  
2011 ◽  
Vol 142 (3) ◽  
pp. 389-399 ◽  
Author(s):  
Agnieszka Waclawik
Keyword(s):  
Growth Factors ◽  
Feedback Loop ◽  
Interferon Γ ◽  
Prostaglandin Synthesis ◽  
Lipid Mediators ◽  
Uterine Receptivity ◽  
Tight Control ◽  
Initial Signal ◽  
Porcine Conceptus ◽  
Proinflammatory Factors

Ovarian progesterone induces essential changes leading to a temporary state of uterine receptivity for conceptus implantation. Estrogens secreted by the porcine conceptus on days 11 and 12 of pregnancy provide the initial signal for maternal recognition of pregnancy and maintenance of a functional corpus luteum (CL) for continued production of progesterone. As prostaglandins F2α(PGF2α) and E2(PGE2) exert opposing actions on the CL, a tight control over their synthesis and secretion is critical either for the initiation of luteolysis or maintenance of pregnancy. One of the supportive mechanisms by which conceptus inhibits luteolysis is changing PG synthesis in favor of luteoprotective PGE2. Conceptus PGE2could be amplified by PGE2feedback loop in the endometrium. In pigs, as in other species, implantation and establishment of pregnancy is associated with upregulation of expression of proinflammatory factors, which include cytokines, growth factors, and lipid mediators. The conceptus produces inflammatory mediators: interferon γ and interferon δ, interleukins IL1B and IL6, and PGs, which probably activate inflammatory pathways in the endometrium. The endometrium responds to these embryonic signals by enhancing further progesterone-induced uterine receptivity. Understanding the mechanisms of pregnancy establishment is required for translational research to increase reproductive efficiencies and fertility in humans and animals.

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