Kidney Development<<>>Urological Development

How to make a nephron

How to make 10⁶ nephrons.

How to connect nephrons from kidney to bladder.

How nephron formation is related to hypoplasia and dysplasia and how these are related to abnormalities of the urinary track.

Concepts

Lineage marker

Epiboly and experiments that investigated the “duct”.

The plasticity of the duct systems.

Induction and Reciprocal Induction

Mesenchymal to epithelial conversion

Monopodial & dipodial branching

Stephen’s Hypothesis and the “shared molecule hypothesis”

The Central Mechanism of Kidney Development is
the Conversion of
Mesenchyme into Epithelia

MET: Kidney and Testis

EMT: Neural Crest, Endocardial cushion, Carcinoma, Damage to Tubules.

Mesenchyme Epithelia

Motile, migratory Sessile

Few Cellular Contacts Tightly Adherent

NCAM E-cadherin, ZO-1

Diffuse Extracellular Matrix Localized Matrix (basal)

Collagen I III Collagen IV

Polarity by leading edge Polarity Apical-Basal

Vimentin IF Cytokeratin IF

Wolffian Duct Forms in One Day

How Does the Wolffian Duct Form So Quickly?

H:A tubule forms in the cranial part of the cord and then the epithelial cells proliferate and migrate caudally.

Exp: Coherent growth of an epithelial cord; very high replication rate in these cells.

H: A wave of Mesenchymal to Epithelial Conversion. 1.Cells could incorporate along the length of the cord as they convert into epithelia.

Exp: the tubule to be a mosaic of cells.

2.Cord is formed and then converts in situ in a two step process.

Exp: We could dissociate cord formation and epithelialization.

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Concepts

Lineage marker

Epiboly and experiments that investigated the “duct”.

The plasticity of the duct systems.

Mesenchymal to epithelial conversion

Induction and Reciprocal Induction

Monopodial & dipodial branching

Stephen’s Hypothesis and the “shared molecule hypothesis”

Wolffian Duct>>?

Changes the surrounding duct cells to express Pax-2.

Pax-2 is required for all subsequent steps.

As the Wolffian duct advances caudally, nephrons appear on either side of the duct. The nephrons form perpendicular to the cord. The are called ‘mesonephric tubules’. 20-30 tubules form. It is functional in amphibia and fish, but in mammals only the cranial 4-6 attach to the Wolffian duct, and the rest will degenerate.

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Reciprocal Induction

Mutual Dependency

Implies that factors made in Mesenchyme>>Ureteric bud>>Mesenchyme

Hence any interruption of the signaling between these compartments must affect both compartments.

Determination of targeting and downstream signaling is complex because a factor may come from the mesenchyme to instruct the ureteric bud to synthesize a factor important in the mesenchyme.

Reciprocal Induction

Ureteric Bud>Mesenchyme

Wnt6, Wnt9a,Wnt-11, FGF-2,9,18, TIMP, IL-6 Cytokines, BMP-7.

Mesenchyme>Ureteric Bud

GDNF, FGF-7, pleiotrophin, BMP-4, HGF, amphiregulin.

Stroma>Ureteric Bud

RA dependent factor, BMP-4, BMP-6.

Ureteric Bud>Stroma

Unknown signal.

Mesenchyme>Stroma

BMP-7.

Stroma>Mesenchyme

Unknown Signal.

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RET

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Two Pathways to Form Epithelia
in the Metanephric Kidney

Mesenchymal Cells into Epithelial Cells-Nephron, A Sequence

1. Proliferation of mesenchymal cells.

2. De novo expression of competency factors (Pax-2, WT-1).

3. De novo expression of conversion factors (Wnt-4).

4. De novo expression of junctional proteins (NCAM>Cad6>E-cadherin>ZO-1).

5. De novo expression of matrix proteins (collagen I/III, Fn >laminin alpha5, collagen IV).

6. De novo expression of cytoskeletal proteins (vimentin>cytokeratin).

Branching Morphogenesis- Ureteric Bud, A Sequence

1. Proliferation of epithelia

2. Transient loss of epithelial organizers such as E-cadherin

3. But retention of other components of polarity such as Zo-1

4. Coherent growth of the tubule.

5. Distinct populations of tip cells which can act as pathfinders, or have different rates of replication. Ret⁺

6. 3 types of branching-terminal bifid, arcade and cortical lateral-Regulatory events?

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Kidney Development<<>>Urological Development

How to make a nephron

How to make 10⁶ nephrons.

How to make the connection from kidney to bladder.

How nephron formation is related to hypoplasia and dysplasia and how these are related to abnormalities of the urinary track.

Concepts

Nephron number is variable, hypolasia, dysplasia

Mesenchymal to epithelial conversion

Lineage marker

Epiboly and experiments that investigated the “duct”.

The plasticity of the duct systems.

Induction and Reciprocal Induction

Monopodial & dipodial branching

Stephen’s Hypothesis and the “shared molecule hypothesis”

Epithelia

Mesenchymal to Epithelial Conversion

Tubule elongation and branching

Tubules-sheets of cells

Tubules being used for multiple purposes.


	How to make a nephron
	How to make 10⁶ nephrons.
	How to connect nephrons from kidney to bladder.
	How nephron formation is related to hypoplasia and dysplasia and how these are related to abnormalities of the urinary track.


	Lineage marker
	Epiboly and experiments that investigated the “duct”.
	The plasticity of the duct systems.
	Induction and Reciprocal Induction
	Mesenchymal to epithelial conversion
	Monopodial & dipodial branching
	Stephen’s Hypothesis and the “shared molecule hypothesis”


	MET: Kidney and Testis
	EMT: Neural Crest, Endocardial cushion, Carcinoma, Damage to Tubules.
	Mesenchyme Epithelia
	Motile, migratory Sessile
	Few Cellular Contacts Tightly Adherent
	NCAM E-cadherin, ZO-1
	Diffuse Extracellular Matrix Localized Matrix (basal)
	Collagen I III Collagen IV
	Polarity by leading edge Polarity Apical-Basal
	Vimentin IF Cytokeratin IF


	H:A tubule forms in the cranial part of the cord and then the epithelial cells proliferate and migrate caudally.
	Exp: Coherent growth of an epithelial cord; very high replication rate in these cells.
	H: A wave of Mesenchymal to Epithelial Conversion. 1.Cells could incorporate along the length of the cord as they convert into epithelia.
	Exp: the tubule to be a mosaic of cells.
	2.Cord is formed and then converts in situ in a two step process.
	Exp: We could dissociate cord formation and epithelialization.


	Changes the surrounding duct cells to express Pax-2.
	Pax-2 is required for all subsequent steps.
	As the Wolffian duct advances caudally, nephrons appear on either side of the duct. The nephrons form perpendicular to the cord. The are called ‘mesonephric tubules’. 20-30 tubules form. It is functional in amphibia and fish, but in mammals only the cranial 4-6 attach to the Wolffian duct, and the rest will degenerate.


	Mutual Dependency
	Implies that factors made in Mesenchyme>>Ureteric bud>>Mesenchyme
	Hence any interruption of the signaling between these compartments must affect both compartments.
	Determination of targeting and downstream signaling is complex because a factor may come from the mesenchyme to instruct the ureteric bud to synthesize a factor important in the mesenchyme.


	Ureteric Bud>Mesenchyme
	Wnt6, Wnt9a,Wnt-11, FGF-2,9,18, TIMP, IL-6 Cytokines, BMP-7.
	Mesenchyme>Ureteric Bud
	GDNF, FGF-7, pleiotrophin, BMP-4, HGF, amphiregulin.
	Stroma>Ureteric Bud
	RA dependent factor, BMP-4, BMP-6.
	Ureteric Bud>Stroma
	Unknown signal.
	Mesenchyme>Stroma
	BMP-7.
	Stroma>Mesenchyme
	Unknown Signal.


	Mesenchymal Cells into Epithelial Cells-Nephron, A Sequence
	1. Proliferation of mesenchymal cells.
	2. De novo expression of competency factors (Pax-2, WT-1).
	3. De novo expression of conversion factors (Wnt-4).
	4. De novo expression of junctional proteins (NCAM>Cad6>E-cadherin>ZO-1).
	5. De novo expression of matrix proteins (collagen I/III, Fn >laminin alpha5, collagen IV).
	6. De novo expression of cytoskeletal proteins (vimentin>cytokeratin).
	Branching Morphogenesis- Ureteric Bud, A Sequence
	1. Proliferation of epithelia
	2. Transient loss of epithelial organizers such as E-cadherin
	3. But retention of other components of polarity such as Zo-1
	4. Coherent growth of the tubule.
	5. Distinct populations of tip cells which can act as pathfinders, or have different rates of replication. Ret⁺
	6. 3 types of branching-terminal bifid, arcade and cortical lateral-Regulatory events?


	How to make a nephron
	How to make 10⁶ nephrons.
	How to make the connection from kidney to bladder.
	How nephron formation is related to hypoplasia and dysplasia and how these are related to abnormalities of the urinary track.


	Nephron number is variable, hypolasia, dysplasia
	Mesenchymal to epithelial conversion
	Lineage marker
	Epiboly and experiments that investigated the “duct”.
	The plasticity of the duct systems.
	Induction and Reciprocal Induction
	Monopodial & dipodial branching
	Stephen’s Hypothesis and the “shared molecule hypothesis”


	Mesenchymal to Epithelial Conversion
	Tubule elongation and branching
	Tubules-sheets of cells
	Tubules being used for multiple purposes.