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Axial Nephron Fate Switching Demonstrates a Plastic System Tunable on Demand

ABSTRACT: The human nephron is a highly patterned tubular structure. Approximately 1 million nephrons form in each kidney during embryonic and fetal development and develop specialized cells that regulate bodily fluid homeostasis, blood pressure, and urine secretion throughout life. This raises the question of how these cells originally develop. Here we interrogate early human nephron patterning using an iPSC-based kidney organoid system that generates hundreds of developmentally synchronized nephron structures. We show that human nephron patterning is controlled by integrated WNT/BMP/FGF signaling. Imposing a WNThigh/BMPlow state established a distal identity that matures into thick ascending loop of Henle cell identities by activating FGF. Simultaneous suppression of FGF signaling reverts cells to a proximal cell-state, thereby indicating the dependence on FGF signaling for distal cell formation in the human nephron. Our system highlights plasticity in nephron identities and mechanisms controlling normal patterning.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283186 | GEO | 2025/08/05

REPOSITORIES: GEO

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Axial Nephron Fate Switching Demonstrates a Plastic System Tunable on Demand

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2025-08-05 | GSE293237 | GEO

Axial Nephron Fate Switching Demonstrates a Plastic System Tunable on Demand [RNA-seq]

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Nephron segmentation and patterning in kidney organoids can be modulated by distinct FGF subfamily members

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Project description:The mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (Flcn) is a causative gene for Birt-Hogg-Dube (BHD) syndrome, which is characterized by a variety of symptoms including renal cysts and cancers. Although deletion of Flcn in the mouse collecting duct has been reported to result in cyst formation, its precise role in the nephron remains unclear. We report here that nephron-specific Flcn knockout mice exhibit cystogenesis along the entire nephron segments, most prominent in the LoH, preceded by an irregularly shaped lumen lined by enlarged epithelia. Single-cell RNA sequencing revealed many upregulated genes, especially in the mutant LoH. These genes include those related to lysosomal activity and mTORC1 activation and are likely targets of TFE3/TFEB. While the double Flcn/Tfe3 knockout only ameliorates the glomerular cysts, the double Flcn/Tfeb knockout dramatically reverses most of the phenotypes along the entire nephron. Thus, Flcn deletion leads to cystogenesis via aberrant TFEB activation. Our findings reveal the essential role of the Flcn-TFEB-mTORC1 signaling pathway in nephron development, particularly in LoH, and shed light on the initial disease state of BHD syndrome.

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Project description:Vertebrate limbs develop by integrating signals that control patterning along three main orthogonal axes. Flank-produced retinoic acid (RA) is initially required for limb induction and establishment of the apical ectodermal ridge (AER), a distal signaling center that produces fibroblast growth factors (FGFs), which are essential for limb growth and distalization. Once the AER is established, RA:FGF antagonism determines the restricted expression of a set of genes that control limb proximodistal patterning. Essential for this antagonism is the activation by FGF of the RA-degrading enzyme CYP26B1 in the distal limb bud. In addition, sonic hedgehog produced from the zone of polarizing activity (ZPA) is essential for distal limb anteroposterior patterning and contributes to RA reduction by cooperating in CYP26B1 activation. Meis transcription factors are expressed in the proximal limb bud, are activated by RA and can regulate proximodistal limb development; however, the mechanisms underlying their activity remain unknown. Here we studied Meis function in the mouse limb bud through Meis2 conditional overexpression and elimination of Meis1 and Meis2. We found that Meis activity is first required for limb bud initiation and the proper establishment of the AER and ZPA signaling centers, and subsequently for the development of proximal limb structures. Functional genomic analyses reveal that Meis is an important conveyor of the RA:FGF antagonism through the regulation of components of the RA and FGF signaling pathways, including CYP26B1. In addition, Meis regulates a set of proximal limb genes controlling proximodistal patterning and differentiation. Our work reveals a regulatory module essential for limb patterning and potentially co-opted in other patterning processes involving RA:FGF antagonism.

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