Multiple roles of mouse Numb in tuning developmental cell fates

Background: Notch signaling regulates multiple differentiation processes an d cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antag onize Notch signaling at binary cell fate decisions of certain cell lineage s. Although overexpression experiments suggested that Numb might also antag onize some Notch activity in vertebrates, the developmental processes in wh ich Numb is involved remained elusive. Results: We generated mice with a homozygous inactivation of Numb. These mi ce died before embryonic day E11.5, probably because of defects in angiogen ic remodeling and placental dysfunction. Mutant embryos had an open anterio r neural tube and impaired neuronal differentiation within the developing c ranial central nervous system (CNS). In the developing spinal cord, the num ber of differentiated motoneurons was reduced. Within the peripheral nervou s system (PNS), ganglia of cranial sensory neurons were formed. Trunk neura l crest cells migrated and differentiated into sympathetic neurons, in cont rast, a selective differentiation anomaly was observed in dorsal root gangl ia, where neural crest-derived progenitor cells had migrated normally to fo rm ganglionic structures, but failed to differentiate into sensory neurons. Conclusions: Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous sys tem, Numb is required for the generation of a large subset of neuronal line ages. The restricted requirement of Numb during neural development in the m ouse suggests that in some neuronal lineages, Notch signaling may be regula ted independently of Numb.