FIGURE 9.

Proposed mechanism of Notch regulation of proximal-distal patterning during lung bud morphogenesis. A, distal epithelial progenitors (in red) exposed to local high levels of Fgf10 activate an Fgf10-Fgfr2b program that results in cell expansion and subsequent induction of Notch1 and Jag ligands. Notch signaling is maintained at the tips by Fgf and in part by Notch-mediated induction of Jag1 in neighbor cells (^*, lateral induction), which contributes to establish a uniform field of Notch activation distally. Activation of Jag-Notch signaling restricts further expansion of distal progenitors. In the forming stalk, Notch1 interaction with Dll1 at the tip-stalk boundary inhibits Notch expression proximally (^**, lateral inhibition) to allow stalk cells to assume a proximal phenotype. Together, these ensure a proper ratio of tip versus stalk cells and proper proximal-distal patterning of the lung. Patterning is also influenced by mesenchymal Notch signaling via a control of levels and distribution of Fgf10 (mechanism not explored here and thus not included in this diagram). B, disruption of Notch signaling results in uncontrolled expansion of distal progenitors and altered proximal-distal patterning of the lung epithelium in which stalk cells assume a distal phenotype.