Term
| What is the tissue of origin of the adult kidneys? |
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Definition
| Sacral extension of intermediate mesoderm that begins at 3.5 weeks (there are also paired cervical and thoraco-lumbar extensions that are transient) |
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Term
| Explain the major events during the embryonic time-course of adult kidney development. |
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Definition
At 3.5 weeks
1) Cervical extension called "Pronephric" or "Mesonephric/Wolffian" duct is present, and is lost after 4th week, becoming the mesoneprhic duct
4-8 weeks
2) Thoracolumbar extension, also called "Mesonephric" duct (originally the "pronephric duct")
3) "Metanephric kidney" arises from Uretic bud (distal end of mesonephric duct), which branches and pentrates the intermediate mesoderm in the sacral region, or the "Metanephric mesenchyme"
4) Kidneys ultimately ascend from the lumbar region to the sacral region in late embryogenesis (switching blood supply from metanephric to mesonephric segmental arteries). |
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Term
| Which adult kidney structures arise from the Ureteric bud and the Metanephric Mesenchyme? |
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Definition
Remember, after 2 months, the Ureteric bud (arising from the thoracolumbar Mesonephric duct) branches and penetrates the sacral intermediate mesoderm called the "Metanephric Mesenchyme."
**Further maturation depends upon MUTUALLY INDUCTIVE signaling**
1) Ureteric bud gives rise to Ureter, Renal Pelvis, Calyses, Collecting ducts and tubules
2) The Metanephric Mesenchyme gives rise to Renal Corpuscles (except blood vessels), LOH, and Proximal and Distal convoluted tubules. |
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Term
| What molecular signaling pathway drives Uteric bud outgrowth and branching prior to penetration of the Metanephric mesenchyme? |
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Definition
1) Glial cell line derived growth factor (GDNF) is secreted by metanephric mesenchyme and binds to RET receptors (T kinase) and GFRA-1 co-receptors on mesonephric duct and uteretic bud cells
2) SLIT2/ROBO2 signaling and BMP4 signaling represses GDNF expression to sacral levels by inhibiting cranial expression |
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Term
| What does "Hirschsprung disease" (intestinal aganglionosis) have to do with Uteretic bud development? |
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Definition
Hirschsprung disease often involves mutations in RET (receptor on mesonephric duct and uteretic bud cells) or GDNF (molecule released by metanephric mesenchyme) mutations cause abnormal Uteretic bud development and thus altered kidney development.
Remember, the U bud gives rise to the Ureters, renal pelvis, calyses, collecting ducts and tubules |
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Term
| What molecular signaling pathway drives metanephric mesenchyme condensation and epithelial cell polarization prior to engulfment of the uteretic bud in embryonic kidney development? |
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Definition
Remember, the Metanephric mesenchyme and Uteretic bud depend upon mutually-inductive signaling.
Wnt signaling from Uteretic bud: binds Frizzled receptor and leads to nuclear accumulation of beta-catenin and transcriptional regulation.
1) Wnt proteins promote mesenchymal to epithelial transition (Wnt9b)
2) Wnt proteins also upregulate GDNF (Wnt11)
3) Polarization of metanephric mesenchymal epithelial cells depends upon Wnt4 as well. |
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Term
| What is the role of Wilms tumor gene 1 (WT1) in early and late phases of metanephric kidney development? |
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Definition
Mutations in WT1 are found in 5-10% of Wilms tumors (most common cause of pediatric kidney cancer), which are composed of clusters of arrested nephron precursors from metanephric mesenchyme.
1) Early
- Regulates GDNF and promotes survival of metanephric mesenchyme progenitors
2) Late
- Suppresses metanephric mesenchyme progenitors, leading to differentiation. |
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Term
| Explain the basic eymbryonic development of the bladder and urethra. |
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Definition
1) At 4-7 weeks, the Cloaca (primitive gut tube), which is continuous with the allantois and the hindgut, becomes partitioned into the anorectal canal (hindgut) and the Urogenital Sinus (Allantois) via the action of mesodermal rearrangements between the Hindgut and Allantois
2) During weeks 7-8, cloacal membrane (originally separating cloaca from amniotic cavity) breaks down and opens Anorectal canal and UGS to amniotic fluid.
3a) Cranial part of UGS becomes bladder
3b) Caudal part of UGS becomes urethra (as well as vestibule in females)
4) As bladder forms from cranial UGS, the ureters get displaced from the mesonephric ducts to the bladder wall (the mesonephric ducts now located inferioly)
5) During second embryonic month, the remnants of the allantois and bladder apex become the urachus or "median umbilical ligament" |
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Term
| What are the ultimate forms of the Urogenital sinus? |
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Definition
Remember, the UGS results from partitioning of the cloaca at 4-7 weeks (other part becomes anorectal canal).
UGS becomes
1) bladder (cranial)
2) urethra (caudal)
3) prostate gland (buds of caudal urethra)
4) lower part of the vagina (solid endodermal outgrowths of UGS) |
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Term
Why can oligohydramnios occur in the context of renal agenesis?
What syndrome will the neonate present with? |
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Definition
1) If renal agenesis is bilateral, due to failure of formation or degeneration of both uteretic buds (RET or EYA1 mutations), the metanephric mesenchyme will not develop and there may be insufficient amniotic fluid volume.
2) Potter sequence or syndrome
- Clubbed feet, craniofacial abnormalities and pulmonary hypoplasia. |
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Term
| Why might a neonate have a duplication of the ureter? |
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Definition
- Premature bifurcation of ureteric bud or formation of two buds.
- One may open normally, and one may open lower (close to neck of bladder), leading to obstructed flow and predisposing to back-flow and infections. |
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Term
| What mutations might cause renal hypoplasia? |
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Definition
| PAX2, SALL1. These mutations are ALSO associated with renal dysplasia |
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Term
| Why might you see a "horseshoe kidney"? |
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Definition
They can't ascend!
Fusion of inferior poles of kidneys on each side (capsule abnormality).
Ascent of kidney is therefore blocked by IMA! |
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Term
| What is Vesico-ureteral reflux (VUR) and what mutations are associated? |
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Definition
Abnormal back-flow from bladder to ureter
- EYA1 and ROBO2 (receptor for SLIT2 that limits expression of GDNF to sacral regions of mesoderm) |
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Term
| What features define Polycystic kidney disease? |
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Definition
Fluid filled cysts and kidney enlargement due to mutations in proteins localized to non-motile cilia or ciliary basal bodies (responsible for regulating cell polarity, cell cycle and Wnt signalling).
Polycystins 1 and 2 (AD PKD) and fibrocystin (AR PKD) mutations
**HNF-1B transcription factor mutations also associated, since they regulate PKD1 and PKD2 expression** |
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