During the development of any organ, a key issue is how to couple proliferation of progenitor cells with differentiation so that an organ of proper size and appropriate constituent cells is formed. We have been examining the role of TGF-ßs in this process using two model systems. The first is development of the Drosophila brain. The second is the development of the mammalian vasculature. In both cases, TGF ß family members mediate the proliferation versus differentiation decision via an unusual cross-pathway signaling network. Normally, TGF-ß signaling pathways are divided into either the BMP or Activin/TGFß branches in terms of the Smad transcription factors that are phosphorylated during signal transduction. The BMP family of ligands signal through Smads1/5/8 while the Activin/TGF-ß branch utilizes Smads2/3. We have found that during Drosophila larval brain development, BMPs actually signal through both the Smad1 branch as well as the Smad2 branch and that the balance regulates and coordinates proliferation and differentiation of neurons versus glia. Likewise, other investigators have found that a similar situation holds during angiogenesis. In this case, it appears that a balance of TGF-ß signaling through the receptor-Smad pairs Alk1/Smad1/5 and Alk5/Smad2, controls the activation versus resolution phase of angiogenesis. In the activation phase, primitive endothelial cells proliferate and migrate, while in the resolution phase they differentiated and recruit smooth muscle. In collaboration with Electra Coucouvanis in the Stem Cell Institute at the University of Minnesota, we have discovered an additional feature of this processwhich is that TGF-ß also activates a Smad independent pathway during angiogenesis involving the Tak1 kinase (TGF beta activated kinase). We are presently trying to determine how the Tak1 pathway interfaces with the Smad pathway to modulate the activation versus resolution phase of angiogenesis. Our observations in Drosophila, together with angiogenesis example in vertebrates, suggest that cross-pathway and non-canonical signaling may be ancient mechanisms by which members of the TGF-ß family couple proliferation with differentiation during organ development.
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Figure 1: A Drosphila brain lobe showing proliferating cells (pH3, green) in the optic centers, photoreceptor axons (24B10, red), and neurons (elav magenta C. zhu)
Figure 2: A Tak1 homozygous mutant mouse embryo showing an edema around the heart (arrow) caused by a failure in angiogenesis.