A Versatile Signal In Vertebrate Embryogenesis: Wnt-4 Regulates Kidney Development, Sex Organ Differentiation, Neuronal Survival And Axonal Guidance

March 02, 1999

Researchers at the Max Planck Institute for Immunobiology, at Harvard University, at Oulu University /Finland and at the University of California characterised the important signalling role of a secreted protein of the Wnt family in kidney development, sex organ differentiation and axonal growth and guidance in vertebrate embryogenesis. (Development 125, 4225-4234, 1998; Nature 397, 405-409, 1999; Science 283, 1180-1183,1999)

The formation of vertebrate organs is a complex process. It is characterised by the interaction of different cells and tissues to assure the concerted program of cell growth, differentiation and morphogenesis which garanties the functional architecture of the adult organ. Cell and tissue interactions are mediated by signalling molecules of various protein classes.

The mammalian kidney has been widely exploited as a model system to study the principles of vertebrate organ formation. Kidney development is characterized by an interaction between an epithelial and a mesenchymal compartment: the Wolffian duct and the nephrogenic mesenchyme. Dependent on signals from the mesenchyme, the ureter will give rise to the adult collecting duct system whereas the mesenchyme upon signals from the ureter will differentiate to form the major part of the nephrons, the functional unit of the excretory system, which is responsible for removal of nitrogenous waste and physiological control of salt balance.

An important family of signalling molecules is encoded by Wnt genes. Wnt proteins are secreted glycoproteins which have been shown to regulate numerous developmental processes like brain formation, limb patterning, and axis formation in the vertebrate embryo.

Classical experiments demonstrated the reciprocal nature of inductive events in the kidney using tissue separation and recombination techniques. The ureteric bud induces the mesenchyme to condense and to form tubules - precursors to nephrons. The mesenchyme in turn promotes ureteric bud proliferation and branching. The ureteric signal can be mimicked by other tissues, in particular the spinal cord.

Andreas Kispert, when postdoc in Andrew McMahon's laboratory at Harvard University and later in his own lab at the Max Planck Institute for Immunobiology in Freiburg/Germany, discovered that Wnt factors are the likely candidates for this tubule inducing activity. Using cell lines expressing various Wnt genes he could induce tubulogenesis in isolated kidney mesenchyme. He further showed that Wnt-4 that was known to be required in kidney development is a mesenchymal factor sufficient for triggering nephron formation in isolated mesenchyme. These experiments allow a new interpretation of the old classical experiments and strengthen the point that Wnt-4 is a central player in the mesenchymal cascade leading to nephron formation.

Sex organ development is unique in vertebrate organogenesis because two different organ systems - the male and female internal and external sex organs, respectively, develop from an indifferent anlage equally present in either sex. Upon the action of the testis determining factor Sry encoded by the Y chromosome, differentiation of the male sex ducts from the Wolffian duct, and degeneration of the Müllerian duct occurs. In females, which lack Sry, the Wolffian duct degenerates whereas the Mülerian duct differentiates into the female sex ducts.

Seppo Vainio, when a postdoc in Andrew McMahon's, discovered that in female newborn embryos male sex ducts instead of female ducts were present. In collaboration with Andreas Kispert he showed that Wnt-4 indeed seems to be critical in suppressing male cell fates in the female embryos. Without Wnt-4, male sex hormone producing cells differentiate in the female gonad. The male sex hormone testosterone leads to the maintenance of the male sex duct system in the female. Additionnally, the anlage of the female duct system, the Mülerian duct, is absent in either sex.

The survival, axonal outgrowth and target innervation of sensory neurons depends on factors secreted by their environment. Neurotrophins are a class of proteins that mediate these functions on neurons as demonstrated by the fact that in the absence of Neurotrophin-3 most sensory neurons are lost before they can reach their target tissues.

Ardem Patapoutian in Louis Reichardt's laboratory at the University of California in San Francisco was investigating the regulation of Neurotrophin-3 expression and found that axons are not required for NT-3 expression but local signals from the environment. In the limb bud signals from the ectoderm, the outer epithelial layer, are responsible for NT-3 expression in the underlying mesenchyme. Using the Wnt expressing cell lines provided by Andreas Kispert from the Max Planck Institute for Immunobiology he could demonstrate that Wnt proteins, in particular Wnt-4, can mimick the ectodermal signal and induce NT-3 expression in isolated limb bud mesenchyme.

These studies have identified Wnt-4 as a key signalling molecule mediating tissue interactions in developmental contexts as diverse as kidney development, sex organ formation, and neuronal growth and axonal guidance.


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