Receptor tyrosine kinases (RTKs) control proliferation and differentiation through their ability to bind and/or phosphorylate intracellular substrates. The repertoire of substrates recruited by different RTK is largely overlapping. It is not clear, therefore, how a cell distinguishes among signals originating from different RTKs. One possibility is that selective availability of substrates participates in the regulation of this process. To gain insight into this issue, we studied the expression pattern, during mouse embryogenesis, of the eps8 and eps15 genes, which encode two recently identified RTK substrates. Both genes are expressed from E 10 in a restricted fashion. eps8 is first expressed in frontonasal neural crest-derived cells, in the mesenchyme of branchial arches and in the liver primordium. At E 12.5-E 14, eps8 is additionally expressed in the central nervous system (CNS) in a regional restricted pattern at the met-mesencephalic transition area and in the developing submandibular salivary glands. eps15 is expressed at E 10 in the liver primordium, in the spinal ganglia and in the encephalic ganglia derived from the hindbrain neural crest. In addition, at E 12.5-E 14, eps15 is expressed, along all the CNS, in the ventricular zone where undifferentiated neuroblasts are located. The regional pattern of developmental expression of these two substrates sharply contrasts with their ubiquitous expression in adults, raising the possibility that their expression during embryogenesis is linked to selective proliferative and/or differentiative responses of specific neuroectodermal regions and body organs.