Disease relevance of numb

• Similarly asymmetric localisation and segregation of the determinant Numb during ganglion mother cell divisions ensure that the progeny sibling neurons attain distinct fates [1].

High impact information on numb

• Here, we describe a Numb- and Neuralized-independent mechanism that acts redundantly in cell-fate specification [2].
• Loss of pon function disrupts Numb localization in muscle progenitors and delays Numb crescent formation in neural precursors [3].
• Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors [3].
• Moreover, ectopically expressed PON responds to the apical-basal polarity of epithelial cells and is sufficient to localize Numb basally [3].
• Asymmetric division of Drosophila neuroblasts, sensory organ precursor cells, and cells in the procephalic neurogenic region involves the segregation of Numb and Prospero proteins into one of the two daughter cells [4].

Biological context of numb

• Neuroblasts in the developing Drosophila CNS asymmetrically localize the cell fate determinants Numb and Prospero as well as prospero RNA to the basal cortex during mitosis [5].
• During asymmetric cell division, the membrane-associated Numb protein localizes to a crescent in the mitotic progenitor and is segregated predominantly to one of the two daughter cells [6].
• Overexpression of Nak in the sensory organs causes both daughters of a normally asymmetric cell division to adopt the same cell fate, a transformation similar to the loss of numb function phenotype and opposite the cell fate transformation caused by overexpression of Numb [6].
• The frequency of cell fate transformation is sensitive to the numb gene dosage, as expected from the physical interaction between Nak and Numb [6].
• We show here that Numb acts in SOP cells by inducing the endocytosis of Sanpodo, a four-pass transmembrane protein that has previously been shown to regulate Notch signalling in the central nervous system [7].

Anatomical context of numb

• Thus, Lgl regulates cell fate by controlling Pon cortical localization, asymmetric localization of Numb and Neuralized, and plasma-membrane localization of Sandopo [8].
• In pins mutants, these epithelial cells were not affected, but neuroblasts showed defects in the orientation of their mitotic spindle and the basal asymmetric localisation of Numb and Miranda during metaphase [9].
• The adaptor protein Numb is necessary for the cell fate specification of progenitor cells in the Drosophila nervous system [10].
• Neuroblasts that delaminate from the embryonic epithelium require lgl to promote formation of a basal Numb and Prospero crescent, which will be asymmetrically segregated to the basal daughter cell upon division to specify cell fate [11].
• In contrast to centrosome positioning, however, Numb and Prospero localization is independent of microtubules [12].

Associations of numb with chemical compounds

• Numb-associated kinase interacts with the phosphotyrosine binding domain of Numb and antagonizes the function of Numb in vivo [6].
• We have identified a putative serine/threonine kinase, Numb-associated kinase (Nak), which interacts physically with the phosphotyrosine binding (PTB) domain of Numb [6].
• Surprisingly, Bazooka controls asymmetric localization of the Numb-anchoring protein Pon, but not spindle orientation, in pI and all subsequent divisions [13].
• Interestingly, the affinity of this peptide for the dNumb PTB domain was increased (Kd = 1.41 +/- 0.10 microM) when the second tyrosine in the sequence was phosphorylated [14].
• The regulation of apoptosis by Numb/Notch signaling in the serotonin lineage of Drosophila [15].

Physical interactions of numb

• In the NB4-2->GMC-1->RP2/sib lineage, one of the well-studied neuronal lineages in the ventral nerve cord, the Notch (N) signaling interacts with the asymmetrically localized Numb (Nb) to specify sibling neuronal fates to daughter cells of GMC-1 [16].
• Mutant forms of alpha-Adaptin that no longer bind to Numb fail to localize asymmetrically and cause numb-like defects in asymmetric cell division [17].
• Two independent amino acid changes that interfere with Shc binding to phosphotyrosine residues do not affect Numb activity in vivo [18].

Co-localisations of numb

• PON is asymmetrically localized during mitosis and colocalizes with Numb [3].

Regulatory relationships of numb

• Our results indicate that when Numb inhibits Notch signaling, cells undergo neuronal differentiation, whereas cells that maintain Notch signaling initiate apoptosis [15].

Other interactions of numb

• Our data suggest that AurA, aPKC, Numb, and Notch function in a pathway that involved a series of negative genetic interactions [19].
• We found that the Numb PTB domain but not the Shc PTB domain interacts with Nak through a peptide of 11 amino acids, implicating a novel and specific protein-protein interaction [6].
• In the absence of nb, cells follow the same fate as they would in the presence of a gain-of-function N allele, such as Ax [20].
• The correct positioning of Numb and the proper orientation of division require Inscuteable (Insc) [21].
• This leads to Ttk expression in the daughter cell that does not inherit Numb [22].

Analytical, diagnostic and therapeutic context of numb

• Those results, together with our observation from immunofluorescence analysis that Numb forms a crescent in the dividing IIa and IIb cells suggest that asymmetric localization of Numb is important for the cell fate determination in all three asymmetric cell divisions in the sensory organ lineage [23].
• Functional analysis of the Numb phosphotyrosine-binding domain using site-directed mutagenesis [18].
• Similarly, in dissociated cell cultures, some retinal neuroepithelial cells divide asymmetrically and distribute Numb to only one of the two daughter cells, suggesting that the dissociated cells can retain their polarity in vitro [24].

References