Development of the Urinary System

Thomas A. Marino, Ph.D. Department of Anatomy and Cell Biology

Temple University School of Medicine

Competencies: Upon completion of this section of the course, the student must be able to:

!• Define the three embryonic kidneys. • Know the developmental fate of the pronephros,

mesonephros and metanephros. • Understand the origin of cells that develop into

the different segments of the kidney tubule. • Compare and contrast the collecting tubule with

the nephron.

Development of the Kidney

• A nephron contains 10,000 cells. • A nephron has at least 12 cell types. • 1 - 3 million collecting tubules are formed.

Development of the Kidney• The development of the pronephros • The development of the mesonephros • The development of the metanephros • The development of the kidneys

Development of the Pronephros

• By day 22 intermediate mesoderm is identified lateral to the paraxial mesoderm.

Intermediate Mesoderm

Development ofthe Kidneys

• Intermediate mesoderm gives rise to nephrotomes or nephric vesicles in the cervical region.

• This is the beginning of the pronephros.

• These are non-functional. • They are vestigial remnants

that disappear by day 24 or 25.

Development of the Kidney

• Glomeruli arise from vessels that branch from the aorta.

Aorta

Development of the Kidneys

• By day 23 intermediate mesoderm (orange and navy) is identified lateral to the paraxial mesoderm (red).

• Intermediate mesoderm is organized into: • pronephros • mesonephrose • metanephros

Development of the Kidneys

• Nephric tubules appear in intermediate mesoderm.

• Tubules have: – Bowman’s capsule – glomerulus – link to mesonephric

duct

Development of the Kidneys• As the mesonephros

develops, mesonephric tubules form and a mesonephric duct develops.

• Mesonephric ducts appear at 24 days.

• These ducts are actually rods of cells that grow caudally.

• By 26 days they have grown to reach the cloaca.

• As they reach the cloaca they begin to develop a lumen. cloaca

Mesonephric duct

Development of the Kidney• A ureteric bud arises off the

mesonepric duct by 28 days. • Ureteric bud connects to the

metanephric blastema by 32 days.

• Mesonephric duct is functional between 6 and 10 weeks.

• Then their fate is dependent upon the gender of the individual.

• In males they will become parts of the male genital duct system.

• In females they mostly regress.

metanephric blastema

Definitive Kidney 1. Development of

the nephron. 2. Development of

the collecting system.

3. Development of the vasculature.

Development of the Kidneys

• The development of the metanephric kidney involves the ureteric bud and the metanephrogenic mesenchyme. – Epithelial-mesenchymal interactions. – Mesenchymal-epithelial transformations.

Development of the Kidney1. Metanephrogenic

mesenchyme forms in the posterior intermediate mesoderm. !

Mesonephric duct

Metanephrogenic mesenchyme

Intermediate Mesoderm

• Lim1, Pax2/8, Odd1 – Help specify

intermediate mesoderm

• Gradients of BMP – Lateral high levels – Medial low levels

• Medial gradient not clear.

Development of the Kidney

1. Metanephrogenic mesenchyme forms in the posterior intermediate mesoderm.

2. It induces ureteric bud from mesonephric duct.

Mesonephric duct

Metanephrogenic mesenchyme

Urerteric bud

Development of the Kidney

• Formation of ureteric bud. – Mesenchymal cells induce the formation of

ureteric bud. – WT-1 is gene that encodes for a zinc-finger

protein that is necessary for kidney formation. – In Wt-1 knockout mice no kidneys or gonads. – Lack of WT-1 appears to destroy the ability of.

the mesenchyme to induce the ureteric bud

Tyrosine kinase receptor RET made by ureteric bud

glial-derived neurotrophic factormade by mesenchyme

Development of the Kidney

1. Metanephrogenic mesenchyme forms in the posterior intermediate mesoderm.

2. It induces ureteric bud from mesonephric duct.

3. Ureteric bud induces overlying mesenchyme to condense around buds.

Mesonephric duct

Metanephrogenic mesenchyme

Urerteric bud

• FGF2 and bone morphogenetic protein 7 (BMP-7) produced by ureteric bud.

• Both block apoptosis. • Stimulate proliferation • Help convert this mesenchyme.

Development of the Kidney

Development of the Kidney

1. Metanephrogenic mesenchyme forms in the posterior intermediate mesoderm.

2. It induces ureteric bud from mesonephric duct.

3. Ureteric bud induces overlying mesenchyme to condense around buds.

4. Mesenchyme differentiates into nephrons.

Mesonephric duct

Metanephrogenic mesenchyme

Urerteric bud

Development of the Kidneys• Week 6 ureteric bud bifurcates 4 times. • Branches coalesce to form major calyces.• 7th week next four branches coalesce to form

minor calyces • By 32 weeks 1 - 3 million collecting ducts form.

Development of the Kidney

• Pax-2 is also induced in condensing mesenchyme.

• If Pax-2 is not induced the mesenchyme will not condense.

• WNT4 also involved.

Development of the Kidney

• Mesenchyme to epithelium conversion – This is accompanied by a change in the

extracellular matrix. – Before induction: Connective tissue matrix

• Type I and III collagen, fibronectin. – After induction: Epithelial matrix

• Laminin and Type IV collagen

Development of the Kidney

• Syndecan and E-cadherin – are involved in the conversion from mesoderm

to epithelium.

Development of the Kidney

1. Metanephrogenic mesenchyme forms in the posterior intermediate mesoderm.

2. It induces ureteric bud from mesonephric duct.

3. Ureteric bud induces overlying mesenchyme to condense around buds.

4. Mesenchyme differentiates into nephrons.

5. Nephrons induce further branching of ureteric bud.

Mesonephric duct

Metanephrogenic mesenchyme

Urerteric bud

Development of the Kidney

• Making the nephron – Connexin 43 is a gap junction protein and is

necessary for connecting cell of S-shaped tube.

– Pax-2 must be turned off or cells will not differentiate.

Development of the Kidneys• Week 6 ureteric bud bifurcates 4 times. • Branches coalesce to form major calyces.• 7th week next four branches coalesce to form

minor calyces • By 32 weeks 1 - 3 million collecting ducts form.This cartoon shows the ureteric bud derivative the collecting duct

connecting to the developing nephron.

Notch plays a role in proximal-distal differentiation of the nephron. It is important in the development of the proximal nephron !Lim1 also must be expressed for the renal vesicle to form. !Lim1 is important for BRN1 expression. !

Renal corpuscle

• The glomerulus needs to develop. – Endothelial cells need to be recruited.

• Podocytes need to differentiate. – Foot processes – Slit diaphragms

• Glomerular basement membrane.

Development of the Kidneys• Week 6 ureteric bud bifurcates 4 times. • Branches coalesce to form major calyces.• 7th week next four branches coalesce to form

minor calyces • By 32 weeks 1 - 3 million collecting ducts form.

Glomerulus• 4 cell types

– Endothelial cell – Mesangial cell – Podocyte – Parietal cells of

Bowman’s capsule.

Signaling

• WT1 • Pod1 • Podocin, Gleep1 and Nephrin • VegF

– Secreted by the podocyte to attract endothelial cells

• PDGF – Stimulate mesangial cells

Basement membrane

– Before induction: Connective tissue matrix • Type I and III collagen, fibronectin.

– After induction: Epithelial matrix • Laminin and Type IV collagen • Type IV collagen shifts from

Øα1 and α2 chains Øα3, α4, and α5 ØChanges here can result in glomerular nephritis

• Regulated by Lmx1b

Podocyte• Nephrin • Podocin • CD2AP • Neph1

Maintain the podocyte foot processes and the filtration slit diaphragms. Also maintain the glomerular basement membrane