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Organogenesis

Coordinating early kidney development: lessons from gene targeting

Nature Reviews Genetics volume 3, pages 533–543 (2002)Cite this article

Key Points

  • The kidney is an excellent model in which to study the mechanisms of organogenesis.

  • During kidney development, the epithelial ureteric buds branch and induce the surrounding mesenchymal cells to transform into epithelium, which goes on to form the functional unit of the kidney, the nephron.

  • The generation of mouse mutants has lead to the discovery of several genetic cascades that regulate early kidney organogenesis in the mouse.

  • Transcription factors such as Wt1, Pax2, Eya1, Sall1 and Foxc1 contribute to the initiation of organogenesis, and Gdnf signals through the Ret receptor to induce ureteric budding and the regulation of its branching, together with other factors, such as pleiotrophin.

  • Cell-surface proteoglycans, such as glypican-3, and enzymes that regulate the synthesis of the proteoglycans side chains, such as Hs2st, are also important in early kidney development.

  • Wnt signalling is essential for tubulogenesis in the kidney and triggers nephrogenesis in vitro. The bone morphogenetic proteins might regulate the proliferation of nephrogenic cells.

  • The stromal compartment of the kidney is also a significant player in coordinating kidney development. Forkhead box D1 and nuclear retinoic acid receptors are expressed in the stroma and are required for proper kidney development.

  • Gene knockouts in the mouse indicate that signalling from the ureteric bud, kidney mesenchyme and stroma regulate kidney development. However, many of the signals that are involved have yet to be discovered.

Abstract

The kidney is widely used to study the mechanisms of organogenesis. Its development involves fundamental processes, such as epithelial branching, induced morphogenesis and cytodifferentiation, which are common to the development of many other organs. Gene-targeting experiments have greatly improved our understanding of kidney development, and have revealed many important genes that regulate early kidney organogenesis, some of which have a role in inherited human kidney disorders. Although our understanding of how the kidney is assembled is still limited, these studies are beginning to provide insights into the genetic and cellular interactions that regulate early organogenesis.

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Figure 1: Morphological stages of early kidney development and some of the genes involved in its development.
Figure 2: Model of genetic interactions during early kidney development.
Figure 3: Marker-gene expression during early kidney development.
Figure 4: Cell-surface heparan sulphate proteoglycans.

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Acknowledgements

We thank S. Kuure (Department of Biomedicine, Biomedicum, University of Helsinki, Finland) and P. Itäranta (Biocenter Oulu and Department of Biochemistry, Linnanmaa, University of Oulu, Oulu, Finland) for the images in figure 3. We acknowledge support from the Academy of Finland, Sigrid Jusélius Foundation and EU programme. We apologize for the failure to cite many important contributions to the field owing to space limitations.

Author information

Authors and Affiliations

  1. Biocenter Oulu and Department of Biochemistry, Linnanmaa, Faculties of Science and Medicine, University of Oulu, P.O. Box 3000, FIN-90014, Finland

    Seppo Vainio

  2. Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Yanfeng Lin

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  1. Seppo Vainio
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Correspondence to Seppo Vainio.

Related links

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DATABASES

Flybase

dally

frizzled

spalt

LocusLink

Amphiregulin

Bmp2

Bmp4

Bmp7

Egf

Emx2

endostatin

Eya1

EYA1

Fgf1

Fgf2

Fgf7

Foxc1

Foxd1

Frizzled-4

Gdnf

Gfra1

Gpc3

Hgf

Hs2st

Met

Notch

Pax2

pleiotrophin

Rara

Rarb

Ret

Sall1

SALL1

sFrp1

sFrp2

Tgf-β

Wg

Wnt2b

Wnt4

Wnt6

Wnt11

Wt1

WT1

OMIM

branchio-oto-renal syndrome

Frasier syndrome

renal dysplasia

Simpson–Golabi–Behmel syndrome

Townes–Brocks syndrome

WAGR syndrome

FURTHER INFORMATION

Encyclopedia of Life Sciences

kidney and renal tract: developmental disorders

The Kidney Development Database

National Institute of Diabetes & Digestive & Kidney Diseases

Glossary

WOLFFIAN DUCT

A duct that originates from the mesonephros, which gives rise to the ureteric bud of the metanephric kidney. The duct persists in males to contribute to parts of the gonad, but regresses in females.

CHORIOALLANTOIC MEMBRANE

A membrane that surrounds bird embryos, which lies adjacent to the egg shell and contributes to gas exchange.

INTERMEDIATE MESODERM

A specific region of embryonic mesoderm that forms the kidney and the sex organs.

METANEPHRIC BLASTEMA

Loosely organized mesenchymal cells that form nephrons in the kidney.

NEPHROGENIC MESENCHYME

Mesenchymal cells adjacent to the tips of the branching ureteric bud that will form the nephrons.

STROMA

Connective tissue that is made up of cells, such as fibroblasts, and matrix, such as collagen.

NEPHRON

The functional unit of the adult kidney that contains the organ's secretory and excretory parts.

GLOMERULUS

The network of blood capillaries in the cup-like end (Bowman's capsule) of the nephron, where waste products are filtered from the blood into the kidney tubule.

COLLECTING DUCT

Structures of the collecting-duct system that drain the nephrons of urine and that derive from the branched ureteric bud.

RENAL PELVIS

A funnel-shaped structure that is formed at one end by the expanded upper portion of the ureter and at the other by the union of the calyxes of the kidney, which receive urine from the collecting ducts. Urine collected here is funnelled through to the ureter, to be collected in the bladder and then excreted.

ENDOTHELIAL CELLS

Flattened cells that grow in a single layer and line blood vessels.

HOMEOBOX

A 180-base-pair sequence that is present in many developmental genes of animals and plants. It encodes a DNA-binding helix–turn–helix motif, indicating that homeobox-containing gene products function as transcription factors.

GLYCOSAMINOGLYCANS

(GAGs). Polysaccharides that comprise repeating disaccharide units of amino-sugar derivatives that are covalently bonded to proteins to function as proteoglycans. Four types of GAG exist according to their sugar residues, and sulphate group numbers and location: chondroitan sulphate and dermatan sulphate; heparin sulphate and heparin; keratan sulphate and hyaluronan.

HEPARAN SULPHATE

A sulphated polysaccharide that is found in cell-surface proteoglycans and is structurally similar to heparin. Heparan sulphates are highly heterogeneous, with different lengths of saccharide chain, levels of sulphation and core carbohydrate sequences.

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Vainio, S., Lin, Y. Coordinating early kidney development: lessons from gene targeting. Nat Rev Genet 3, 533–543 (2002). https://doi.org/10.1038/nrg842

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