Biology Reference
In-Depth Information
receptors and of other substrates. The phosphorylated tyrosine residues act as
docking sites for various molecules, that subsequently transduce the signal in
the cytoplasm (for a review of ErbB signalling see Yarden and Sliwkowski,
2001). Signals given by ErbB receptors can stimulate motility, proliferation,
suppress apoptosis or induce differentiation. ErbB3, the receptor expressed at
high levels in neural crest cells, recognizes neuregulins as ligands. The
cytoplasmic domain of ErbB3 has homologies to tyrosine kinases, but the
receptor appears to have little or no tyrosine kinase activity. Upon ligand
binding, ErbB3 heterodimerizes with other ErbB receptors with activatable
tyrosine kinase domains, which phosphorylate ErbB3 in trans and enable
ErbB3 to signal. Neuregulins bind not only ErbB3, but also a different
receptor of the family, ErbB4. However ErbB3 and ErbB4 are frequently
expressed in distinct cell types and tissues and can therefore take over different
and non-overlapping functions. In particular, ErbB3 but not ErbB4 is
expressed in neural crest cells, and ErbB3 takes over decisive functions in
development of this cell type.
Neuregulins, the ligands bound by the ErbB3 receptor, constitute a small
family of EGF-like factors. Nrg1, the first identified member of the family, has
been studied extensively. In cell culture, various biological activities of Nrg1
have been observed and were used to purify and characterize the factor: Nrg1
can induce growth of glial cells and was therefore also named GGF (Glial
Growth Factor; Shah et al., 1994). It can induce growth and differentiation of
epithelial cells and was therefore named NDF (Neu Differentiation Factor;
Marikovsky et al., 1995) or Heregulin (Holmes et al., 1992), and it can induce
the expression of acetylcholine receptor in muscle cells and was therefore also
named ARIA (Acetylcholine Receptor Inducing Activity; Falls et al., 1993).
My laboratory has investigated the functional role of Nrg1 and ErbB
receptors and has demonstrated that the gene plays important roles in
development of neural crest cells.
For this, we used mice as a model organism, and generated mutant alleles of
ErbB3, ErbB2 and Nrg1 by the use of homologous recombination and the
embryonal stem cell technology (Meyer and Birchmeier, 1995; Riethmacher
et al., 1997; Britsch et al., 1998). Since the null-mutations interfere with
survival of embryos, late developmental functions cannot be investigated in
such mutant mice. We have therefore also used other, more sophisticated
genetic techniques to overcome this limitation (Woldeyesus et al., 1999;
Garratt et al., 2000). In general, we observe similar, if not identical,
phenotypes in neural crest cells and their derivatives in ErbB2, ErbB3 and
Nrg1 mutant mice. These results provide the genetic proof that Nrg1 signals
via ErbB2/ErbB3 receptor heteromers in neural crest cells. It should be noted
that Nrg1 can also signal via the ErbB2/ErbB4 receptor heteromers, for
instance during heart development, but here only the roles of Nrg1/ErbB
receptors in neural crest cells will be discussed.
