Numb influences cell fate by regulating alpha-adaptin-mediated endocytosis of Notch. D. Berdnik 1, T. Török 2, M. Gonzáles-Gaitán 3, J.A. Knoblich 1. 1) IMP, A-1030 Vienna, Austria; 2) Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, H-6701 Szeged, Hungary; 3) MPI for molecular cell biology and genetics, D-01307 Dresden, Germany.
During asymmetric cell division in the Drosophila peripheral nervous system the Numb protein localises asymmetrically and segregates into one of the two daughter cells. In this cell, it induces a particular cell fate by repressing signal transduction via the Notch receptor. Numb binds to Notch, but how it regulates Notch signaling is unclear.
We show here that alpha-Adaptin, a protein involved in receptor-mediated endocytosis, is required for Notch repression by Numb. In vitro and in vivo binding studies show that a-Adaptin binds to Numb via its C-terminal appendage domain. Like Numb, alpha-Adaptin localises asymmetrically in dividing neural precursor cells and segregates preferentially into one daughter cell. alpha-Adaptin localisation is disrupted in numb mutants or in alpha-adaptin alleles that mutate or delete the appendage domain and affect binding to Numb. While alpha-adaptin null mutants are cell-lethal, these mutants do not affect general endocytosis and cell viability. Instead, they cause cell fate transformations similar to the ones observed in numb mutants and act genetically upstream of Notch and downstream of Numb.
We suggest that Numb acts as a linker that recruits alpha-Adaptin to Notch on one side of the cell cortex during asymmetric cell division and downregulates Notch by receptor mediated endocytosis.