Cell Fates and the Dilemma of Common Signaling

Science's STKE  10 Oct 2000:
Vol. 2000, Issue 53, pp. tw1
DOI: 10.1126/stke.2000.53.tw1

How can similar signals sent by a receptor tyrosine kinase (RTK) elicit different outcomes (differentiation fates) for various cells? Flores et al. studied the ability of the Drosophila epidermal growth factor receptor (DER), an RTK, to specify the expression of the Drosophila Pax2 (D-Pax2) gene whose expression is restricted to pigment and cone cells within ommatidia. The authors identified an enhancer element for D-Pax2 that is necessary for D-Pax2 expression in cone cells. However, expression required the activity of the transcription factors Suppressor of Hairless (involved in Notch signaling), Pointed (which supplants the effects of the transcription inhibitor Yan), and Lozenge, as well as their cognate DNA binding sites. Removing the ability of any one of these components to function prevented the expression of D-Pax2. Similarly, Xu et al. studying prospero expression in Drosophila found that although DER signaling was necessary, there was a further requirement for Pointed and Lozenge activity in a prospero enhancer. Thus, in the absence of Pointed or Lozenge binding, the enhancer was unable to mediate the expression of prospero. Finally, Halfon et al. examined the fate switches determined by DER and another RTK termed Heartless (a fibroblast growth factor receptor homolog) by observing the specific expression of even-skipped within the dorsal mesoderm layer. The authors found that Wingless and Decapentaplegic [homologs to Wnt and transforming growth factor β (TGF-β), respectively] were required before RTK activation in order to direct specific gene expression. However, even-skipped expression depended upon the further involvement of the transcription factors Pointed, Mad, and dTCF binding to a specific region within an even-skipped enhancer. As is becoming a recurring theme, the disruption of the binding of any of the transcription factors to the enhancer prevented the specific expression of the gene studied, in this case even-skipped. Thus, these studies demonstrate that the activation of several different signaling pathways impinging on the same genetic end point is important for generating specific gene expression and differentiation into specific cell fates. Simon writes a particularly lucid overview of these papers and their implications.

Flores, G.V., Duan, H., Yan, H., Nagaraj, R., Fu, W., Zou, Y., Noll, M., and Banerjee, U. (2000) Combinatorial signaling in the specification of unique cell fates. Cell 103: 75-85. [Online Journal]

Xu, C., Kauffmann, R.C., Zhang, J., Kladny, S., and Carthew, R.W. (2000) Overlapping activators and repressors delimit transcriptional response to receptor tyrosine kinase signals in the Drosophila eye. Cell 103: 87-97. [Online Journal]

Halfon, M.S., Carmena, A., Gisselbrecht, S., Sackerson, C.M., Jiménez, F., Baylies, M.K., and Michelson, A.M. (2000) Ras pathway specificity is determined by the integration of multiple signal-activated and tissue-restricted transcription factors. Cell 103: 63-74. [Online Journal]

Simon, M.A. (2000) Receptor tyrosine kinases: Specific outcomes from general signals. Cell 103: 13-15. [Online Journal]