The numb gene protein product controls binary cell fate decisions in the peripheral and central nervous systems of both invertebrates and mammals during neurogenesis.
One daughter cell, generally that receiving the Numb, is able to adopt a neuronal fate and innervate the developing nervous system.
Numb exerts its functional role on cell fate decisions by antagonizing Notch signaling activities.
[13] In support of this, Numb's ability to ubiquinate Notch1 directly correlated with its functional inhibition of Notch1 signaling activities.
Numb and Itch work in concert to promote the ubiquitination of the full-length membrane-tethered Notch receptor prior to activation.
[6] Numb has been studied most extensively in Drosophila, in particular in the context of their sensory organ precursors and ganglion mother cells.
The asymmetric division of the SOP into daughter cells with distinct fates is dependent upon the distribution of Numb.
Numb is distributed uniformly in the cytoplasm until mitotic division, when it is selectively localized to the anterior pole of the cell.
The mother neuroblast divides along the apical-basal axis, with Numb localizing basally and ending up in the GMC.
[18] In mice embryos mutant for Numb, early neurons emerge in the expected spatial and temporal pattern but fail to maintain a sufficient pool of proliferating progenitors and nearly deplete the population of dividing cells shortly after the onset of neurogenesis.
[19] These embryos display precocious neuron production in the forebrain and defects in neural tube closure, dying around embryonic day 11.5.
However, other studies have shown overexpression of Numb in the mammalian neural crest MONC-1 stem cell line biases neuronal differentiation, consistent with what is observed in drosophila.
The mammalian brain has accounted for this by producing isoforms of Numb that maintain progenitor populations in addition to those which support neuronal differentiation.
Studies using the mouse embryonic P19 cell line have shown isoforms with the short proline rich region (PRR) domain promote neuronal differentiation, while those with the long PRR domain promote cell proliferation and prevent differentiation.
Restoration of Numb function, or manipulation of enzymes in the ubiquitin mechanism, are some possible research directions for the treatment of certain cancer types.
[6] In approximately half of all human mammary carcinomas, Numb-mediated suppression of Notch signaling is lost due to Numb ubiquitination, tagging it for proteasomal degradation.
[24] Numb acts as an oncogene suppressor, inhibiting tumor cell proliferation through suppression of Notch signaling.
Increased Notch signaling is observed in tumors where Numb activity has been lost and retrovirally mediated transient overexpression of Numb protein in these tumors restored basal levels of Notch signaling and significantly reduced their colony-forming abilities.
Thus, the biological antagonism between Notch and Numb signaling that controls the proliferative/differentiative balance of many cell lineages appears to play a role in human breast carcinogenesis and perhaps other types of tumorigenesis.
[6] Neural precursors are generated in proliferative zones, before migrating to directed locations where they undergo maturation and become functional neurons.
[25] Once activated, aPKC phosphorylates Numb, thus promoting a positive feed-forward response that potentiates Numb-chemotactic receptor binding and subsequent endosomal complex formation.