Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation.
Two receptor tyrosine kinases, ErB-3 and ErbB-4, mediate signaling by Neu differentiation factors (NDFs, also called neuregulins), while ErbB-1 and ErbB-2 serve as co-receptors. We show that the two NDF/neuregulin receptors differ in spatial and temporal expression patterns: The kinase-defective receptor, ErbB-3, is expressed primarily in epithelial layers of various organs, in the peripheral nervous system, and in adult brain, whereas ErbB-4 is restricted to the developing central nervous system and to the embryonic heart. An example of alternating expression of the two receptors is provided by the developing cerebellum: During postnatal cerebellar development, ErbB-4 expression slightly decreases along with a decline in NDF transcription, whereas ErbB-3 expression commences after the peak of neurogenesis. To study functional differences, we established primary brain cultures and found that ErbB-3 was expressed only in oligodendrocytes, whereas ErbB-4 expression was shared by oligodendrocytes, astrocytes and neurons. Blocking the action of endogenous NDF in vitro, by using a soluble form of ErbB-4, accelerated neurite outgrowth in both primary cultures and in neuronal-type cultures of the P19 teratocarcinoma, suggesting an inhibitory effect of NDF on neural differentiation. Apparently, ErbB-3 is associated with proliferation of P19 cells, whereas ErbB-4 correlates with a differentiated phenotype. We conclude that the two NDF receptors play distinct, rather than redundant, developmental and physiological roles.
Pinkas-Kramarski
R
R
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Eilam
R
R
Alroy
I
I
Levkowitz
G
G
Lonai
P
P
Yarden
Y
Y
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000378:metabolism* / Q000502:physiology; D006023:Glycoproteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D020880:Neuregulins; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009924:Organ Culture Techniques; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4
D006023:Glycoproteins; D006131:Growth Inhibitors; D008024:Ligands; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4