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 of the 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

Aorta • Glomeruli arise from vessels that branch from the 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 Kidney

1. Metanephrogenic mesenchyme forms in the posterior intermediate mesoderm. !

Metanephrogenic mesenchyme Mesonephric duct 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. Urerteric 2. It induces ureteric bud from bud mesonephric duct. Metanephrogenic mesenchyme Mesonephric duct 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 glial-derived neurotrophic factor made by ureteric bud made by mesenchyme Development of the Kidney

1. Metanephrogenic mesenchyme forms in the posterior intermediate mesoderm. Urerteric 2. It induces ureteric bud from bud mesonephric duct. 3. Ureteric bud induces overlying mesenchyme to Metanephrogenic condense around buds. mesenchyme Mesonephric duct Development of the Kidney

• 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

1. Metanephrogenic mesenchyme forms in the posterior intermediate mesoderm. Urerteric 2. It induces ureteric bud from bud mesonephric duct. 3. Ureteric bud induces overlying mesenchyme to Metanephrogenic condense around buds. mesenchyme 4. Mesenchyme differentiates Mesonephric into nephrons. duct 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. Urerteric 2. It induces ureteric bud from bud mesonephric duct. 3. Ureteric bud induces overlying mesenchyme to Metanephrogenic condense around buds. mesenchyme 4. Mesenchyme differentiates Mesonephric into nephrons. duct 5. Nephrons induce further branching of ureteric 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 This• By cartoon 32 weeks shows 1the - 3ureteric million bud collecting derivative ducts the collecting form. 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 Maintain the podocyte foot processes and the filtration slit diaphragms. • Podocin Also maintain the glomerular basement membrane • CD2AP • Neph1