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Renal > 2 Renal Embryology > Flashcards

2 Renal Embryology Flashcards

1
Q

Developmental events in urinary system embryogenesis

  • 3 weeks
  • 4 weeks
  • 5 weeks
  • 6 weeks
  • 7 weeks
  • 9-10 weeks
A
  • 3 weeks
    • Gastrulation
    • Subdivision of the mesodermal germ layer into paraxial, intermediate, & lateral mesoderm
  • 4 weeks
    • Formation of the pronephric duct (–> mesonephric duct)
    • Appearance & regression of pronephric tubules
    • Appearance of mesonephric tubules
  • 5 weeks
    • Appearance of adult kindey precursors (metanephric mesenchyme & ureteric bud)
  • 6 weeks
    • Cranial (thoracic) mesonephros undergoes massive regression
    • Caudal (lumbar) mesonephric tubules function
    • Metanephric excretory units begin to form
    • Kidneys begin to ascend
  • 7 weeks
    • Division of the cloaca complete
    • Regression of the allantois
    • Urogenital component of the cloacal membrane ruptures
  • 9-10 weeks
    • Kidneys reach a lumbar position
    • Mesonephros ceases to function & regresses
    • Metanephric kidney begins to produce urine
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2
Q

Development of the kidneys & ureters

  • Intermediate mesoderm
  • Elongated duct
A
  • Intermediate mesoderm (3.5 weeks)
    • Extends to each side of the embryo from cervical to sacral regions
    • Gives rise to 3 paired sets of excretory structures
      • Only the sacral components will develop into adult kidneys
      • Cervical & throaco-lumbar components are transient
  • Elongated duct (4 weeks)
    • Forms within the intermediate mesoderm on each side of the embryo
    • Extends from the cervial region to the expanded end of the hindgut (cloaca)
    • On each side of the embryo, interactions b/n this duct & the adjacent intermediate mesoderm lead to the differentiation of excretory tubules
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3
Q

Kidney development

  • When most events occur
  • Direction of development
  • Mesonephric duct
A
  • When most events occur
    • In the first 2 months
  • Direction of development
    • Cranial to caudal
  • Mesonephric duct
    • Long duct extending from the cervical to caudal region (claoca)
    • 3 sets of nephrons/tubules
      • Pronephros (top)
      • Mesonephros (middle)
      • Metanephros (definitive kidney + ureters)
        • Metanephrogenic mesenchyme
        • Ureteric bud (buds off mesonephric duct)
    • Tubules next to the mesonephric duct
      • Either associate w/ gonads or degenerate
    • Mesonephric duct –> vas deferens, epididymis, etc. while nephrons disappear
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4
Q

Pronephric kidney (pronephros)

  • Consists of…
  • Function
  • Early stages associated duct
  • Later stages associated duct
A
  • Consists of small epithelial clusters (rudimentary tubules) in the cervical region
  • Nonfunctional in humans
    • Only present during the 4th week
  • Early stages associated duct: pronephric duct
  • Later stages associated duct: mesonephric (Wolffian) duct
    • Primary association: mesonephros
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5
Q

Mesonephric kidney (mesonephros)

  • Consists of
  • Associated duct
  • Mesonephric tubules
  • Cranial mesonephric tubules
  • Caudal mesonephric tubules
A
  • Consists of tubules that form a large swelling in the thoraco-lumbar region
  • Associated duct: mesonephric duct
    • Original pronephric duct
    • Regresses in females
    • forms the epididymis & vas deferens in males
  • Mesonephric tubules
    • Resemble simplified adult excretory tubules
    • Function during 2nd month
  • Cranial mesonephric tubules
    • Regress shortly after they form
  • Caudal mesonephric tubules
    • Ultimately regress
    • Some cellular components contribute to gonads in males
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6
Q

Metanephric kidney (metanephros)

  • General
  • Two embryonic components that contribute to its formation
A
  • General
    • Definitive kidney
  • Two embryonic components that contribute to its formation
    • Ureteric bud
      • Emerges as a bud off the distal end of the mesonephric duct
      • Each bud penetrates intermediate mesoderm in the sacral region
    • Metanephric mesenchyme (blastema)
      • Intermediate mesoderm
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7
Q

Organisms that have certain kidneys

  • Pronephric kidney
  • Mesonephric kidney
  • Metanephric kidney
A
  • Pronephric kidney
    • Less developed vertebrates
  • Mesonephric kidney
    • Amphibians & fish
  • Metanephric kidney
    • Humans & birds
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8
Q

Development of the ureteric bud

A
  • Ureteric bud emerges from the mesonephric duct
  • Undergoes repeated branching & elongation
  • Empties into the expanded cloaca
  • Bud & branches –> ureter, renal pelvis, calyses, collecting ducts, & tubules
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9
Q

Development of the metanephric mesenchyme

A
  • Metanephric mesenchyme condenses around the tips of the ureteric bud & its branches
  • Transforms into epithelial cells
  • Differentiates into the nephrons of the kidney
  • –> renal corpuscle (except blood vessels), LOH, & proximal & distal convoluted tubules
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10
Q

Inductive signals

A
  • Differentiation of the ureteric bud & the metanephric mesenchyme depends on mutually inductive signals
  • Signals from metanephric mesenchyme –> elongation & branching of the ureteric bud
  • Signals from the ureteric bud –> aggregation of metanephric mesenchyme cells & their subsequent differentiation into nephrons
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11
Q

Ascent of the kidneys & arterial blood supply

A
  • During 6-10 weeks (late embryogenesis)
    • Kidneys ascend from a sacral to lumbar position
  • During ascent, metanephric kidneys are supplied by segmental arteries that originally supplied the mesonephros
    • These vessels are reduced to a single pair of renal arteries in the adult
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12
Q

GNDNF-RET signaling

  • GDNF (glial cell line derived growth factor)
  • What limits expression/function of GDNF to sacral regions
  • Hox genes
A
  • GDNF (glial cell line derived growth factor)
    • Secreted by metanephric mesenchyme (mesenchyme –> bud)
    • Activates the RET receptor (a tyrosine kinase) & GFRA1 (its co-receptor) on mesonephric duct & ureteric bud cells
    • Drives ureteric bud outgrowth & branching by influencing cell movement & proliferation
  • What limits expression/function of GDNF to sacral regions
    • Signaling via SLIT2 & its receptor ROBO2 repress GDNF expression at cranial levels
    • BMP4 signaling inhibits RET signaling in cranial parts of the mesonephric duct
    • Gremlin (BMP inhibitor) blocks BMP signaling in the metanephric mesenchyme & allows outgrowth in the region
  • Hox genes (esp Hox11)
    • Influence GDNF expression
    • May be necessary for specifying metanephric identity (rather than pronephric or mesonephric)
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13
Q

GNDNF-RET signaling mutations

  • Carriers of RET or GDNF mutations
  • Gene EYA1 mutations
  • Gene PAX2 mutations
  • Gene SALL1 mutations
  • ROBO2 mutations
  • BMP4 mutations
A
  • Carriers of RET or GDNF mutations
    • Hirschsprung disease (intestinal aganglionosis)
  • Gene EYA1 mutations
    • Defect: renal agenesis or hypoplasia
    • Syndrome: branchio-oto-renal (BOR)
  • Gene PAX2 mutations
    • Defect: renal hypoplasia
    • Syndrome: renal coloboma
    • Expression patterns are controlled by sonic hedgehog signaling
  • Gene SALL1 mutations
    • Defect: renal hypoplasia
    • Syndrome: townes-brocks
    • Expression patterns are controlled by sonic hedgehog signaling
  • ROBO2 mutations
    • Vesicoureteral reflux (VUR)
    • Megaureter
    • Dysplastic kidneys
  • BMP4 mutations
    • Congenital anomalies of the kidney & urinary tract (CAKUT)
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14
Q

Wnt signaling

  • General
  • Wnt expression
  • Deregulated Wnt signaling
A
  • General
    • Signals from the ureteric bud influence metanephric mesenchyme development
    • Signal in the opposite direction (bud –> mesenchyme) to induce nephron formation
  • Wnts expressed in the ureteric bud…
    • Induce metanephric mesenchyme aggregation
    • Promote a mesenchymal to epithelial transition, proliferation of mesenchyme cells, & differentiation into the nephron (Wnt9b)
  • Deregulated Wnt signaling –> cystic kidney diseases
    • Frame shift mutation in the Wnt pathway component TCF2 –> enlarged kidnesy displaying cysts
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15
Q

Wilms tumor gene 1 (WT1)

  • Early stages
  • Later stages
  • Mutations in WT1
A
  • Early stages
    • Regulates GDNF
    • Promotes survival of metanephric mesenchyme progenitors
  • Later stages
    • Inhibits proliferation of these cells –> nephron differentiation
    • Develops & matures podocytes
  • Mutations in WT1 –> Wilms tumors
    • Most common pediatric kidney cancer
    • Develop from clusters of mesenchyme (nephrogenic rests) that represent arrested nephrogenic progenitors or stem cells
    • Loss of WT1 –> arrest nephron precursors in multipotent progenitor state
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16
Q

Development of the bladder & urethra

  • Cloaca
  • Cloaca is partitioned into…
  • Cloacal membrane
A
  • Cloaca
    • Central player in the development of hte bladder & urethra
    • Expanded end of the primitive gut tube
    • Continuous w/ the allantois & hindgut
  • 4-7 weeks: Cloaca is partitioned into…
    • Anorectal canal (dorsal): continuous w/ hindgut
    • Urogenital sinus (UGS) (ventral): continuous w/ allantois
      • Allantois: thin diverticulum that extends into the connecting stalk & eventually disappears
    • Septation depends on signaling b/n epithelial & mesenchymal tissues
      • Mediated by Sonic hedgehog (Shh)
  • Cloacal membrane
    • Initiallys eparates the cloaca from teh amniotic cavity
    • 7-8 weeks: breaks down to open the cavities ot he urogenital sinus & anal canal to the amnion
17
Q

Development of the bladder & urethra

  • Cranial urogenital sinus
  • Caudal urogenital sinus
  • Internal linings of these structures
  • Lateral mesodermal tissue
  • Epithelial tag of tissue
A
  • Cranial urogenital sinus
    • –> bladder
  • Caudal urogenital sinus
    • Pelvic or genital portion
    • –> urethra (male)
    • –> uretrha & vestibule of the vagina ( female)
  • Internal linings of these structures
    • Derived from the endoderm of the urogenital sinus
  • Lateral mesodermal tissue
    • –> muscles & connective tissue
  • Epithelial tag of tissue
    • –> distal tip of the male urethra
  • Allantois
    • –> urachus (median umbilical ligament)
18
Q

Development of the bladder & urethra

  • Ureter displacement
  • Outcome of ureter displacement
  • Allantois & bladder apex outcome
  • Prostate gland origin
  • Lower part of the vagina origin
A
  • Ureter displacement
    • As the bladder forms, ureters –> displaced from the mesonephric ducts to the bladder wall
  • Outcome of ureter displacement
    • Ureters acquire a distinct & separate entry into the bladder
    • Entry of the mesonephric duct (presumptive vas deferens) –> positioned inferior to that of the ureter
  • Allantois & bladder apex outcome
    • Regress –> remnants –> ligamentous band (“urachus,” “median umbilical ligament”)
  • Prostate gland origin
    • Originates as buds from the prostatic region of the urethra
  • Lower part of the vagina origin
    • Solid endodermal outgrowths of UGS
19
Q

Malformations of the urinray system

A
  • Congenital anomalies of kidney or lower urinary tract (CAKUT)
    • Common (1/250 live births, 1/100 fetuses
  • Renal agenesis
  • Duplication of the ureter
  • Renal hypoplasia
  • Renal dysplasia
  • Accessory renal arteries
  • Pelvic kidney
  • Horseshoe kidney
20
Q

Renal agenesis

  • General
  • Mutations
  • Unilateral agenesis
  • Bilateral agenesis
A
  • General
    • Failure of formation or degeneration of the ureteric bud
    • Absence of appropriate signals –> metanephric mesenchyme doesn’t differentiate
  • Associated w/ mutations in RET or EYA1
  • Unilateral agenesis –> asymptomatic
  • Bilateral agenesis –> oligohydramnios
    • Insufficiency in amniotic fluid volume –> mechanical compression of developing fetus
    • –> potter sequence / syndrome
      • Clubbed feet, craniofacial abnormalities, & pulmonary hypoplasia
21
Q

Duplication of the ureter

A
  • Premature bifurcation of the ureteric bud or formation of two ureteric buds
  • –> one ureter may open normally, one may open lower (bladder neck or urethra
  • –> ureter may become enlarged due to obstructed urine flow
  • –> may be back-flow of urine (vesi-ureteral reflux, VUR) & frequent infections
22
Q

Renal hypoplasia & dysplasia

  • Renal hypoplasia
  • Renal dysplasia
  • Both
A
  • Renal hypoplasia
    • Kidney contains fewer than normal nephrons (small kidneys)
    • Mutations: PAX2, SALL1 (transcription factors that affect GDNF signaling)
  • Renal dysplasia
    • Kidney contains undifferentiated tissue &/or cysts (kidney doesn’t form)
    • Mutations: PAX2, SALL1
  • Both
    • May be associated w/ abnormal ureter-bladder connections
    • May have resulted from misplaced ureteric buds
23
Q

Accessory renal arteries

A
  • Transient embryonic renal arteries fail to regress
    • Multiple renal arteries come off the aorta into the kidneys
    • Sometimes arteries that were present when kidneys were further down remain
  • Normally: kidneys ascend & blood supply changes
24
Q

Pelvic & horseshoe kidney

A
  • Pelvic kidney
    • Failure of kidney to ascend
  • Horseshoe kidney
    • Fusion of inferior poles of the kidnesy on each side
    • Cause: abnormality in the kidney capsule
    • Ascend of kidney is blocked by the inferior mesenteric artery
25
Q

Vesico-ureteral reflux (VUR)

  • General
  • Primary vs. secondary
  • Mutations
A
  • General
    • Backwards flow of urine from the bladder to the ureters
    • One of the more commonly detected congenital anomalies
    • Associated w/ frequent infections
  • Primary vs. secondary
    • Primary VUR: abnormality in the valve mechanism at the uretero-bladder junction
    • Secondary VUR: obstruction near the uretero-pelvic junction
  • Mutations
    • EYA1, ROBO2, RET, Hoxd13
26
Q

Polycystic kidney disease (PKD)

  • General
  • Causes
    • General
    • Autosomal dominant PKD
    • Autosomal recessive PKD
  • Kidney epithelia
  • During growth & development
  • Renal cyst mutations
  • Bardet-beidl syndrome (BBS)
A
  • General
    • Formation of fluid filled cysts & kidney enlargement
    • Timing of cyst formation ranges from the prenatal period through adulthood
  • Causes
    • Mutations in proteins localized to non-motile cilia or ciliary basal bodies
      • Primary cilia that are mutated
        • Mechanosensors that sense flow
        • Involved in signaling, cell cycle, cell polarity, etc.
      • –> increase in cell proliferation & loss of oriented cell division
    • Autosomal dominant PKD: polycystis 1 & 2
    • Autosomal recessive PKD: fibrocystin
  • Kidney epithelia
    • Solitary cilia appear to function as mechanosensors that detect & transmit signals about fluid flow in tubules to the cell body
    • Involves eliciting a Ca signal
  • During growth & development
    • Cilia may regulate cell polarity, cell cycle, & Wnt signaling
  • Renal cyst mutations
    • HNF-1B: transcription factor that regultaes cystic genes (PKD1 & PKD2), Wnts, & nephron patterning genes
  • Bardet-beidl syndrome (BBS)
    • Cystic kidney disease associated w/ mutations in BBS proteins that normally regulate trafficking of proteins to cilia
27
Q

Normal & malformations of the urethra & bladder

A
  • Normal
    • Bladder is initially associated w/ the rectral canal
    • Cloacal membrane breaks down
    • If bladder & rectal canal aren’t separated correctly –> malformations & abnormal connections
  • Urorectal atresia / fistula
  • Cloaca malformation
  • Urachal fistula, sinus, cyst
  • Exstrophy of the bladder
  • Prune belly syndrome
28
Q

Urorectal atresia / fistula

  • General
  • Possible causes
  • Female
  • Male
A
  • General
    • Abnormal communicaiton b/n the rectum & urethra, vagina, or bladder
  • Possible causes
    • Ectopic positioning &/or size of the cloaca
    • Missing dorsal cloaca
    • Abnormal Shh signaling
  • Female
    • Rectovestibular fistula: abnormal connection b/n rectum & vestibule fo the vagina
    • Rectovaginal: anal canal empties into the developing vagina
  • Male
    • Rectourethral
    • Rectovesical
29
Q

Cloaca malformation & urachal fistula / sinus / cyst

  • Cloaca malformation
  • Urachal fistula / sinus / cyst
A
  • Cloaca malformation
    • No division of the cloaca –> single common channel (females only)
    • Possible cause: abnormal Shh or EYA1 signaling
  • Urachal fistula / sinus / cyst
    • Persistence of part or all of the lumen of the urachus or allantois
    • If allantois doesn’t close up & degenerate, it may remain open –> cyst / fistula
30
Q

Exstrophy of the bladder & prune belly syndrome

  • Exstrophy of the bladder
  • Prune belly syndrome
A
  • Exstrophy of the bladder
    • Defect in the anterior body wall –> bladder is open at the anterior body surface (abdominal region)
    • Possible causes
      • Insufficient tissue proliferation in the anterior body wall
      • Abnormally large cloacal membrane
  • Prune belly syndrome
    • Partial or complete lack of abndominal muscle & urinary tract dilation (rare)
    • Causes the overlying skin to appear rinkled

Renal (24 decks)

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