GO:0090189 regulation of branching involved in ureteric bud morphogenesis: Kidney Development Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0090189 describes any process that modulates the rate, frequency or extent of branching of the ureteric bud, the epithelial tube that gives rise to the ureter and kidney collecting system.
• Ureteric bud branching is controlled by reciprocal signaling between the metanephric mesenchyme and the ureteric bud epithelium, including RET/GFRA1, MAPK/ERK, proteoglycans and secreted factors [1,2,4,5].
• Key positive and negative regulators include ASH2L-dependent RET/GFRA1 activity, pleiotrophin, sulfated proteoglycans, semaphorin3a and embigin [1,2,5,6,8].
• Disruption of ureteric bud branching regulation causes congenital kidney malformations such as renal agenesis, hypoplasia and dysplasia [1,4,7].
• The process is studied with mouse genetic models, organ culture, live imaging, transcriptomics and CRISPR-based perturbation [1,2,6,8].
• CRISPR knockout, point-mutation, knock-in and overexpression models allow causal testing of candidate regulators in ureteric bud morphogenesis [1,6].
Description
GO:0090189, regulation of branching involved in ureteric bud morphogenesis, is a biological process term that captures any process modulating the rate, frequency or extent of ureteric bud branching. The ureteric bud is an epithelial tube that emerges from the metanephric duct and undergoes repeated branching to form the ureter and the collecting tubules of the kidney [3,7]. Because branching determines final nephron number and urinary drainage, its regulation is central to kidney development and congenital disease [1,4,7]. Researchers study this term to understand how mesenchymal and epithelial signals are integrated during organogenesis [3,5]. The process is regulated by extracellular matrix components, growth factors, receptor tyrosine kinase signaling and transcription-associated complexes [1,2,4,5,8]. This article summarizes the definition, mechanism, key genes, disease links and experimental methods for GO:0090189.
regulation of branching involved in ureteric bud morphogenesis At A Glance
| GO ID | GO:0090189 |
|---|---|
| GO term | regulation of branching involved in ureteric bud morphogenesis |
| Ontology | biological_process |
| Synonym | none |
| Major function | Modulates the rate, frequency or extent of ureteric bud branching during kidney development |
| Anatomical context | Ureteric bud epithelium and surrounding metanephric mesenchyme [3,7] |
| Downstream structures | Ureter and kidney collecting tubules [3,7] |
| Representative regulators | RET/GFRA1, ASH2L, pleiotrophin, sulfated proteoglycans, semaphorin3a, embigin [1,2,5,6,8] |
| Associated signaling | MAPK/ERK and receptor tyrosine kinase signaling [1,4] |
What Is GO:0090189?
GO:0090189 is defined as any process that modulates the rate, frequency or extent of branching involved in ureteric bud morphogenesis, the process in which the branching structure of the ureteric bud is generated and organized. The ureteric bud is an epithelial tube that grows out from the metanephric duct; the bud elongates and branches to give rise to the ureter and kidney collecting tubules [3,7]. In practice, this term covers positive and negative regulation of bud initiation, elongation, bifurcation and subsequent arborization [3,7].
Why Is regulation of branching involved in ureteric bud morphogenesis Important in Cell Biology?
Regulation of ureteric bud branching is important because it sets the architectural blueprint of the kidney collecting system and influences nephron endowment [3,7]. Perturbations in this process are linked to congenital anomalies of the kidney and urinary tract, including renal agenesis, hypoplasia and dysplasia [1,4,7]. Understanding GO:0090189 therefore informs developmental biology, disease modeling and regenerative nephrology [1,4,6].
• Determines ureter and collecting duct architecture [3,7].
• Controls final nephron number and kidney size [3,7].
• Links to congenital kidney malformations such as renal agenesis and hypoplasia [1,4].
• Involves receptor tyrosine kinase signaling that is druggable in principle [1,4].
• Requires extracellular matrix and proteoglycan remodeling.
• Is modulated by secreted mesenchymal factors such as pleiotrophin.
• Is inhibited by guidance cues such as semaphorin3a.
• Involves cell-surface proteins such as embigin in early kidney development.
• Provides a model for branching morphogenesis in other organs.
• Offers CRISPR-tractable targets for developmental studies [1,6].
What Happens During regulation of branching involved in ureteric bud morphogenesis?
Initiation and outgrowth of the ureteric bud
In simple terms: The kidney's drainage tube starts as a small bud that pushes out from a duct.
The ureteric bud emerges from the metanephric duct and begins to elongate into the surrounding mesenchyme [3,7]. This early outgrowth is a prerequisite for all subsequent branching and is influenced by reciprocal epithelial-mesenchymal signals [3,5]. Regulation at this stage sets the position and number of initial branches.
Bifurcation and arborization
In simple terms: The bud splits repeatedly to build a tree-like collecting system.
After outgrowth, the ureteric bud undergoes bifurcation and repeated arborization to generate the collecting duct tree [3,7]. The rate and pattern of these branching events are the direct output measured for GO:0090189 [3,7]. Architectural patterns in branching morphogenesis have been described across species and organs.
RET/GFRA1 and MAPK/ERK signaling
In simple terms: A receptor on the bud surface receives growth signals that tell it to branch.
RET/GFRA1 signaling activity is required for ureteric bud morphogenesis, and ASH2L controls branching through regulation of RET/GFRA1 activity in mouse models. MAPK/ERK signaling downstream of receptor tyrosine kinases regulates renal differentiation and branching responses. Perturbing this axis alters bud branching frequency and extent [1,4].
Extracellular matrix and proteoglycan control
In simple terms: The material around the bud helps or hinders its branching.
Sulfated proteoglycans regulate ureteric bud branching morphogenesis in the developing kidney. Intracellular and extracellular mechanisms together modulate bud morphogenesis. Matrix remodeling therefore acts as a permissive and instructive layer of regulation [2,3].
Secreted modulators and guidance cues
In simple terms: Messenger proteins from nearby tissue can speed up or stop branching.
Pleiotrophin was identified as a mesenchymal factor involved in ureteric bud branching morphogenesis. Semaphorin3a inhibits ureteric bud branching morphogenesis, providing a negative regulatory input. Embigin is involved in the regulation of early mouse kidney development, adding a further cell-surface modulator.
Key Genes Involved in GO:0090189 regulation of branching involved in ureteric bud morphogenesis
The following genes and proteins have published roles in regulating ureteric bud branching morphogenesis.
| Gene | Major Role | Research Relevance |
|---|---|---|
| RET | Receptor tyrosine kinase required for ureteric bud morphogenesis | Central node for branching regulation; ASH2L controls its activity |
| GFRA1 | Co-receptor for GDNF in RET signaling | Modulates RET/GFRA1 signaling activity in branching |
| ASH2L | Controls ureteric bud morphogenesis via RET/GFRA1 signaling | Epigenetic regulator linking chromatin to branching |
| PTN | Mesenchymal factor involved in ureteric bud branching | Secreted modulator of branching morphogenesis |
| SEMA3A | Inhibits ureteric bud branching morphogenesis | Negative regulator and guidance cue |
| EMB | Involved in early mouse kidney development | Cell-surface regulator of early kidney development |
| MAPK1 | MAPK/ERK signaling in renal differentiation | Downstream effector of RTK signaling |
| MAPK3 | MAPK/ERK signaling in renal differentiation | Downstream effector of RTK signaling |
| GDNF | Ligand for RET/GFRA1 in kidney development | Upstream input to RET signaling |
| HS6ST1 | Heparan sulfate modification affecting proteoglycan function | Modifies sulfated proteoglycan regulation of branching |
| NDST1 | Heparan sulfate biosynthesis enzyme | Impacts proteoglycan-dependent branching |
| EXT1 | Heparan sulfate polymerase | Affects sulfated proteoglycan regulation |
| SDC1 | Syndecan proteoglycan | Cell-surface proteoglycan in branching regulation |
| GPC3 | Glypican proteoglycan | Modulates growth factor signaling in branching |
| FGF10 | Mesenchymal growth factor in kidney development | Extracellular regulator of bud morphogenesis |
| BMP4 | Signaling factor influencing branching | Modulates branching pattern |
| WNT9B | Epithelial signal in ureteric bud development | Regulates bud outgrowth and branching |
How Is regulation of branching involved in ureteric bud morphogenesis Regulated?
Regulation of ureteric bud branching is itself regulated at multiple levels. ASH2L controls ureteric bud morphogenesis through regulation of RET/GFRA1 signaling activity, linking chromatin-associated complexes to receptor tyrosine kinase output. MAPK/ERK signaling downstream of receptor tyrosine kinases regulates renal differentiation and branching responses. Extracellularly, sulfated proteoglycans and secreted factors such as pleiotrophin and semaphorin3a provide positive and negative inputs [2,5,8]. Cell-surface proteins such as embigin further modulate early kidney development.
regulation of branching involved in ureteric bud morphogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| RET | Congenital kidney malformation via altered branching | Knockout and point-mutation mouse models |
| GFRA1 | Impaired RET/GFRA1 signaling in ureteric bud morphogenesis | Knock-in reporter and knockout models |
| ASH2L | Branching defects through RET/GFRA1 regulation | Conditional knockout mouse |
| SEMA3A | Inhibition of ureteric bud branching | Overexpression and knockout models |
| EMB | Early kidney developmental defects | Knockout mouse and organ culture |
Congenital anomalies of the kidney and urinary tract
Disruption of ureteric bud branching regulation is associated with congenital anomalies of the kidney and urinary tract, including renal agenesis and hypoplasia [1,4,7]. Because branching determines collecting system architecture, defects can cause urinary drainage abnormalities [3,7]. Mouse models with altered RET/GFRA1 or MAPK/ERK signaling show renal differentiation defects [1,4].
Renal dysplasia and hypoplasia
Abnormal branching frequency or extent can lead to renal dysplasia and hypoplasia [3,7]. Proteoglycan and growth factor perturbations alter branching in developing kidney explants [2,5]. These models help define how regulatory imbalance translates into structural kidney disease [2,5].
Relevance to regenerative nephrology
Understanding GO:0090189 informs efforts to rebuild collecting duct structures from stem or progenitor cells [3,7]. Signaling nodes such as RET/GFRA1 and MAPK/ERK are candidate targets for directing branching in vitro [1,4]. Cell-surface modulators such as embigin may influence early kidney progenitor behavior.
From regulation of branching involved in ureteric bud morphogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate gene required for ureteric bud branching? | CRISPR knockout in mouse or cell model [1,6] |
| Does a specific variant alter branching regulation? | Point-mutation knock-in model |
| Where and when is a regulator expressed? | Tagged knock-in reporter [1,6] |
| Does excess regulator increase branching? | Overexpression model [5,8] |
| Which pathways mediate the branching effect? | Organ culture with pathway inhibitors [2,4] |
| What transcriptional changes accompany branching? | RNA-seq of mutant versus control kidneys [1,6] |
How to Study the regulation of branching involved in ureteric bud morphogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Mouse knockout | Requirement of a gene for branching | Causal testing of regulators |
| Organ culture | Branching rate and pattern ex vivo [2,5] | Testing secreted and matrix factors [2,5] |
| Live imaging | Dynamic branching events | Quantifying arborization |
| RNA-seq | Transcriptional changes after perturbation | Pathway discovery |
| Phospho-protein assays | RET/GFRA1 and MAPK/ERK activity [1,4] | Signaling validation [1,4] |
| Immunohistochemistry | Protein localization in bud and mesenchyme [1,6] | Spatial expression analysis [1,6] |
| CRISPR perturbation | Gene function in cultured or animal models [1,6] | Candidate gene screening [1,6] |
Mouse genetic models
Knockout and conditional alleles in mice are used to test requirement of genes such as ASH2L and RET/GFRA1 in ureteric bud morphogenesis. These models allow assessment of branching number, pattern and downstream signaling [1,4].
Kidney organ culture and live imaging
Embryonic kidney explants can be cultured and imaged to quantify branching events over time [2,5]. This approach has been used to show effects of proteoglycans, pleiotrophin and semaphorin3a on branching [2,5,8].
Transcriptomics and signaling assays
RNA-seq and phospho-signaling assays reveal changes in RET/GFRA1 and MAPK/ERK activity after perturbation [1,4]. These readouts connect molecular changes to branching phenotypes [1,4].
Proteoglycan and matrix analysis
Biochemical and genetic manipulation of sulfated proteoglycans is used to test their regulatory role in branching. Such studies link extracellular matrix composition to bud morphogenesis [2,3].
How CRISPR Can Be Used to Study GO:0090189 regulation of branching involved in ureteric bud morphogenesis
Knockout
CRISPR knockout of candidate regulators such as ASH2L or RET pathway components can test their requirement for ureteric bud branching. Loss-of-function models reveal whether a gene is necessary for normal branching rate and extent [1,6].
Point Mutation
Point-mutation knock-in can model specific variants in regulators like RET or GFRA1 to assess their impact on branching. Such models help distinguish gain-of-function from loss-of-function effects.
Knock-in
Tagged knock-in reporters allow visualization of regulator expression during ureteric bud morphogenesis [1,6]. This supports spatial and temporal analysis of branching regulation [1,6].
Overexpression
Overexpression of secreted factors such as pleiotrophin or semaphorin3a can test sufficiency and inhibitory effects on branching [5,8]. These models complement knockout studies [5,8].
How EDITGENE Supports regulation of branching involved in ureteric bud morphogenesis Research
Researchers studying regulation of branching involved in ureteric bud morphogenesis-related genes often need to determine whether a candidate gene is causally involved in branching, which variant alters function, or where the gene is expressed during kidney development. EDITGENE provides CRISPR-based cell and animal models to address these questions with publication-ready validation.
Contact EDITGENE today to design your custom CRISPR model for regulation of branching involved in ureteric bud morphogenesis research.
Frequently Asked Questions About regulation of branching involved in ureteric bud morphogenesis
What is GO:0090189?
GO:0090189 is the Gene Ontology term for regulation of branching involved in ureteric bud morphogenesis, covering any process that modulates the rate, frequency or extent of ureteric bud branching.
What is ureteric bud branching?
Ureteric bud branching is the process in which the epithelial bud from the metanephric duct elongates and branches to form the ureter and kidney collecting tubules [3,7].
What genes are involved in regulation of branching involved in ureteric bud morphogenesis?
Published regulators include RET, GFRA1, ASH2L, PTN, SEMA3A, EMB and MAPK/ERK pathway components [1,4,5,6,8].
How is ureteric bud branching regulated?
It is regulated by reciprocal epithelial-mesenchymal signaling, receptor tyrosine kinase pathways such as RET/GFRA1 and MAPK/ERK, extracellular matrix proteoglycans and secreted factors [1,2,4,5,8].
Why is ureteric bud branching important for kidney disease?
Defects in branching regulation are linked to congenital kidney malformations such as renal agenesis, hypoplasia and dysplasia [1,4,7].
What methods study GO:0090189?
Mouse genetics, kidney organ culture, live imaging, RNA-seq, phospho-signaling assays and CRISPR perturbation are commonly used [1,2,4,6,8].
Does semaphorin3a affect ureteric bud branching?
Yes, semaphorin3a inhibits ureteric bud branching morphogenesis.
What is the role of proteoglycans in ureteric bud branching?
Sulfated proteoglycans regulate ureteric bud branching morphogenesis in the developing kidney.
Can CRISPR be used to study ureteric bud branching?
Yes, CRISPR knockout, point-mutation, knock-in and overexpression models can test candidate regulators of branching [1,6].
What signaling pathway controls ureteric bud branching?
RET/GFRA1 and downstream MAPK/ERK signaling are key pathways in ureteric bud morphogenesis [1,4].
Conclusion
GO:0090189, regulation of branching involved in ureteric bud morphogenesis, is a central developmental process that determines kidney collecting system architecture [3,7]. Its regulation involves RET/GFRA1 and MAPK/ERK signaling, proteoglycans, and secreted modulators such as pleiotrophin and semaphorin3a [1,2,4,5,8]. Understanding these mechanisms has direct implications for congenital kidney disease and regenerative nephrology [1,4,7]. CRISPR-based models provide a rigorous path to test causal roles of candidate regulators [1,6].
References
- 1. Zhao Z et al.. 2023. ASH2L Controls Ureteric Bud Morphogenesis through the Regulation of RET/GFRA1 Signaling Activity in a Mouse Model.. J Am Soc Nephrol 34(6):988-1002 PMID: 36758123
- 2. Steer DL et al.. 2004. Regulation of ureteric bud branching morphogenesis by sulfated proteoglycans in the developing kidney.. Dev Biol 272(2):310-27 PMID: 15282150
- 3. Davies J. 2001. Intracellular and extracellular regulation of ureteric bud morphogenesis.. J Anat 198(Pt 3):257-64 PMID: 11322719
- 4. Kurtzeborn K et al.. 2019. MAPK/ERK Signaling in Regulation of Renal Differentiation.. Int J Mol Sci 20(7) PMID: 30974877
- 5. Sakurai H et al.. 2001. Identification of pleiotrophin as a mesenchymal factor involved in ureteric bud branching morphogenesis.. Development 128(17):3283-93 PMID: 11546745
- 6. Talvi S et al.. 2026. Embigin is involved in the regulation of early mouse kidney development.. Sci Rep 16(1) PMID: 41673303
- 7. al-Awqati Q et al.. 1998. Architectural patterns in branching morphogenesis in the kidney.. Kidney Int 54(6):1832-42 PMID: 9853247
- 8. Tufro A et al.. 2008. Semaphorin3a inhibits ureteric bud branching morphogenesis.. Mech Dev 125(5-6):558-68 PMID: 18249526
