Asymmetric division – the process through which a precursor cell divides to produce two daughter cells of distinct fates – is a basic mechanism used throughout the animal and plant kingdoms to create cell-type diversity. In flies, mice, and almost certainly man the integrated activities of the Notch signaling pathway and the intrinsic cell fate determinant Numb regulate the asymmetric division of many precursors in multiple tissues. Notch/Numb-mediated asymmetric divisions result in daughter cells of distinct fates due to differences in the amplitude of Notch signaling activity between the two daughter cells. One daughter cell exhibits high-levels of Notch signaling, which triggers this cell to adopt a specific fate, termed the “A” cell fate. The other daughter cell exhibits low-levels of Notch signaling, and this cell adopts an alternate fate, termed the “B” cell fate.
How do the two daughter cells come to exhibit such different levels of Notch signaling activity? Upon precursor division, Numb segregates exclusively into the “B” daughter cell, where it functions to inhibit the reception and/or transmission of Notch signaling. Thus, the presence of Numb ensures that Notch signaling is kept low in this cell, and as a result this cell adopts the “B” fate. Conversely, the absence of Numb in the “A” cell permits high-level Notch signaling in this cell, which induces this cell to adopt the “A” fate. Both daughter cells express Notch and can respond to Delta signaling, as in the absence of Numb both daughter cells adopt the Notch-dependent “A” fate. Thus, the asymmetric segregation of Numb into one of two daughter cells is critical to the faithful execution of asymmetric divisions.
But, how does Numb inhibit Notch signaling? This question gains interest when one considers that the Notch signaling pathway regulates a myriad of developmental events and cells involved in executing each of these events express both Notch and Numb, however loss of function studies reveal that Numb normally only inhibits Notch signaling during asymmetric divisions. Work from our lab suggests that the answer to this question, at least in flies, revolves around Sanpodo – a four-transmembrane protein. Sanpodo is expressed exclusively in asymmetrically dividing cells and is necessary for productive Notch signaling in the “A” cell during asymmetric divisions, in accord with the limited expression profile of Sanpodo no other Notch-dependent event requires spdo function for its execution. Our genetic studies have shown that Sanpodo exerts opposite effects on Notch signaling in a context-dependent manner: in the absence of Numb, as occurs in the “A” cell, we have found that Sanpodo potentiates Notch signaling activity; in contrast, in the presence of Numb, as occurs in the “B” cell, Sanpodo enables Numb to inhibit Notch signaling activity. Numb appears to mediate its effect on Notch signaling by regulating the subcellular localization of Sanpodo, as in the absence of Numb Sanpodo preferentially localizes to the cell membrane, whereas in its presence Sanpodo preferentially localizes to cytoplasmic vesicles. Present work in the lab focuses on identifying the mechanistic basis through which Sanpodo both promotes and inhibits Notch signaling activity depending on context via the identification of factors that associate with Sanpodo.