Biology subjects

Huh, S.-H.

Publications and source records attributed to Huh, S.-H..

5 recordsLinked to original sources

bioRxiv2026

Mechanism of Renal Cyst Initiation and Progression Through ETV Transcription Factors and Hedgehog Signaling

Renal cysts are categorized as non-pathogenic simple cysts and pathogenic malignant cysts based on their pathophysiological status. Cyst formation is divided by cyst initiation and cyst progression/promotion. Pathogenic cysts are thought to be developed through continuous initiation followed by progression until pathogenic status is achieved. Although many genetic and environmental factors are identified to cause pathogenic cyst formation, the mechanisms that discriminate cyst initiation and progression are poorly understood. Using genetic mutation models of ETV transcription factors, ETV1, ETV4, and ETV5, and a pharmacological inhibitor of hedgehog signaling, cyclopamine, we identified one of the mechanisms regulating cyst initiation and progression. Nephron specific deletion of ETV4 and ETV5 initiated cyst formation. However, cyst initiation did not continue as animals grow, and a limited number of the initial cysts underwent further growth. Additional deletion of ETV1 was required for continuous initiation in addition to promotion of cyst growth. Furthermore, administration of cyclopamine attenuated promotion of cyst progression but had little effect on cyst initiation. Therefore, we provide evidence that cyst initiation and progression is genetically and molecularly distinct and can be modulated. This information provides new insight into how to control renal cyst initiation and progression and can be used to suppress pathogenic cyst growth.

developmental biology↗

bioRxiv2020

Tumor-free elongation of mammalian nephrogenesis by excess fetal GDNF

Due to poor regenerative capacity of adult kidneys, nephron endowment defined by the nephrogenic program during the fetal period dictates renal and related cardiovascular health throughout life. We show that the neurotropic factor GDNF, which is in clinical trials for Parkinsons disease, is capable of prolonging the nephrogenic program beyond its normal cessation without increasing the risk of kidney tumors. Our data demonstrates that excess GDNF expands the nephrogenic program by maintaining nephron progenitors and nephrogenesis in postnatal mouse kidneys. GDNF, through its transcriptional targets excreted from the adjacent epithelium, has a major effect on nephron progenitor self-renewal and maintenance; abnormally high GDNF inhibits nephron progenitor proliferation, but lowering its level normalizes the nephrogenic program to that permissive for nephron progenitor self-renewal and differentiation. Based on our results, we propose that the lifespan of nephron progenitors is determined by mechanisms related to perception of GDNF and other signaling levels.

developmental biology↗

bioRxiv2020

Mesenchymal ETV Transcription Factors Regulate Cochlear Length

Mammalian cochlear development encompasses a series of morphological and molecular events that results in the formation of a highly intricate structure responsible for hearing. One remarkable event occurs during development is the cochlear lengthening that starts with cochlear outgrowth around E11 and continues throughout development. Different mechanisms contribute to this process including cochlear progenitor proliferation and convergent extension. We previously identified that FGF9 and FGF20 promote cochlear lengthening by regulating auditory sensory epithelial proliferation through FGFR1 and FGFR2 in the periotic mesenchyme. Here, we provide evidence that ETS-domain transcription factors ETV4 and ETV5 are downstream of mesenchymal FGF signaling to control cochlear lengthening. Next generation RNA sequencing identified that Etv1, Etv4 and Etv5 mRNAs are decreased in the Fgf9 and Fgf20 double mutant periotic mesenchyme. Deleting both Etv4 and Etv5 in periotic mesenchyme resulted in shortening of cochlear length but maintaining normal patterning of organ of Corti and density of hair cells and supporting cells. This recapitulates phenotype of mesenchymal-specific Fgfr1 and Fgfr2 deleted inner ear. Furthermore, analysis of Etv1/4/5 triple conditional mutants revealed that ETV1 does not contribute in this process. Our study reveals that ETV4 and ETV5 function downstream of mesenchymal FGF signaling to promote cochlear lengthening.

developmental biology↗

bioRxiv2020

Nephron progenitor maintenance is controlled through FGFs and Sprouty1 Interaction

The nephron progenitor cells (NPCs) give rise to all segments of functional nephrons and are of great interest due to their potential as a source for novel treatment strategies for kidney disease. Fibroblast growth factor (FGF) signal plays pivotal roles in generating and maintaining NPCs during kidney development. However, molecule(s) regulating FGF signal during nephron development is not known. Sprouty (SPRY) is an antagonist of receptor tyrosine kinases. During kidney development, SPRY1 is expressed in the ureteric buds (UBs) and regulates UB branching by antagonizing Ret-GDNF signal. Here, we provide evidence that SPRY1 expressed in NPCs modulates activity of FGF signal in NPCs and regulates NPC stemness. Haploinsufficiency of Spry1 rescues bilateral renal agenesis and premature NPC differentiation caused by loss of Fgf9 and Fgf20. In addition, haploinsufficiency of Spry1 rescues NPC proliferation and cell death defects induced by loss of Fgf9 and Fgf20. In the absence of SPRY1, FGF9 and FGF20, another FGF ligand, FGF8 promotes nephrogenesis. Deleting both Fgf8 and Fgf20 results in kidney agenesis and defects in NPC proliferation and cell death. Rescue of loss of Fgf9 and Fgf20 induced renal agenesis by Spry1 haploinsufficiency was reversed when one copy of Fgf8 was deleted. These findings indicate the importance of the balance between positive and negative signal during NPC maintenance. Failure of the balance may underlie some human congenital kidney malformation. Significance StatementNephrons are functional units of kidney to filter blood to excrete wastes and regulate osmolarity and ion concentrations. Nephrons are derived from nephron progenitors. Nephron progenitors are depleted during kidney development which makes it unable to regenerate nephrons. Therefore, understanding signaling molecules regulating nephron progenitor generation and maintenance is of great interest for the future kidney regenerative medicine. Here, we show that Sprouty1 regulates nephron progenitor maintenance by inhibiting FGF signal. Deletion of Sprouty1 rescues renal agenesis and nephron progenitor depletion in the Fgf9/20 loss-of-function kidneys. Further decrease of FGF signal by deleting one copy of Fgf8 makes kidneys irresponsive to Sprouty1 resulting in failure of nephron progenitor maintenance. This study thus identifies the reciprocal function of FGF-Sprouty1 signal during nephron progenitor development.

developmental biology↗

bioRxiv2018

Sox2 and FGF20 define a temporal separation between specification and differentiation required for organ of Corti development

The mouse organ of Corti develops in two steps: progenitor specification and differentiation. Fibroblast Growth Factor (FGF) signaling is important in this developmental pathway, as deletion of FGF receptor 1 (Fgfr1) or its ligand, Fgf20, leads to the loss of hair cells and supporting cells from the organ of Corti. However, whether FGF20-FGFR1 signaling is required during specification or differentiation, and how it interacts with the transcription factor Sox2, also important for hair cell and supporting cell development, has been a topic of debate. Here, we show that while FGF20-FGFR1 signaling functions during progenitor differentiation, FGFR1 has an FGF20-independent, Sox2-dependent role in specification. We also show that a combination of reduction in Sox2 expression and Fgf20 deletion recapitulates the Fgfr1-deletion phenotype. Furthermore, we uncovered a strong genetic interaction between Sox2 and Fgf20, especially in regulating the development of hair cells and supporting cells towards the basal end and the outer compartment of the organ of Corti. To explain this genetic interaction and its effects on the basal end of the organ of Corti, we provide evidence that decreased Sox2 expression delays specification, which begins at the organ of Corti apex, while Fgf20-deletion results in premature onset of differentiation, which begins near the organ of Corti base. Thereby, Sox2 and Fgf20 interact to ensure that specification occurs before differentiation towards the cochlear base. These findings reveal an intricate developmental program regulating organ of Corti development along the basal-apical axis of the cochlea. Author summaryThe mammalian cochlea contains the organ of Corti, a specialized sensory epithelium populated by hair cells and supporting cells that detect sound. Hair cells are susceptible to injury by noise, toxins, and other insults. In mammals, hair cells cannot be regenerated after injury, resulting in permanent hearing loss. Understanding genetic pathways that regulate hair cell development in the mammalian organ of Corti will help in developing methods to regenerate hair cells to treat hearing loss. Many genes are essential for hair cell and supporting cell development in the mouse organ of Corti. Among these are Sox2, Fgfr1, and Fgf20. Here, we investigate the relationship between these three genes to further define their roles in development. Interestingly, we found that Sox2 and Fgf20 interact to affect hair cell and supporting cell development in a spatially-graded manner. We found that cells toward the outer compartment and the base of the organ of Corti are more strongly affected by the loss of Sox2 and Fgf20. We provide evidence that this spatially-graded effect can be partially explained by the roles of the two genes in the precise timing of two sequential stages of organ of Corti development, specification and differentation.

developmental biology↗