New roles for Notch in tuberous sclerosis
Warren S. Pear
Warren S. Pear
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Commentary

New roles for Notch in tuberous sclerosis

Abstract

Tuberous sclerosis complex (TSC) is a dominantly inherited disease that is characterized by the growth of multiple benign tumors that are often difficult to treat. TSC is caused by mutations that inactivate the TSC1 or TSC2 genes, which normally function to inhibit activation of mammalian target of rapamycin signaling. In this issue of the JCI, two studies reported by Karbowniczek et al. and Ma et al. link TSC inactivation with activated Notch signaling (see the related articles beginning on pages 93 and 103, respectively). Using a variety of approaches, both studies show that inactivation of TSC leads to Notch1 activation. Furthermore, studies in tumor cells suggest that inhibiting Notch slows growth of the tumor cells. Although much remains to be learned about the precise mechanisms by which TSC loss leads to Notch activation, the newly identified link of TSC to Notch provides the rationale for testing Notch inhibitors in TSC-associated tumors.

Authors

Warren S. Pear

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Figure 2

TSC inhibition or Rheb activation results in Notch gain-of-function phenotypes during Drosophila sensory organ development.

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TSC inhibition or Rheb activation results in Notch gain-of-function phen...
(A) Overview of Drosophila ESO development. The SOP (pI) cell undergoes a Notch-dependent asymmetric division to create two daughter cells, pIIa and pIIb. The Notch inhibitor, Numb, is asymmetrically distributed between the two daughter cells; thus, the pIIa cell (lower levels of Numb) results from the induction of Notch signaling, and the pIIb cell (higher levels of Numb) results from lower Notch signaling (i.e., the default state in the absence of Notch induction). Loss of Notch during pI differentiation results in the bald (or bristle loss) phenotype, due to the inability of the pI cell to form the external cuticular structures. Each of the pII cells then undergoes a subsequent, Notch-dependent round of asymmetric division. pIIa divides first, to give rise to the bristle and socket cells. pIIb then divides, to give rise to the sensory neuron and sheath cell. Loss of Notch signaling in the pIIa division results in duplication of the bristle cell, whereas loss of Notch signaling in the pIIb division results in two neurons. The reciprocal phenotypes are produced in Notch gain-of-function mutants. The four cells of the ESO, which results from 3 successive asymmetric divisions, are also depicted. This model is greatly simplified and does not include the multiple proteins that modify the outcome of Notch signaling. (B) As reported by Karbowniczek et al. (9), loss of TSC or Rheb activation in the pI (SOP) cell resulted in loss of the pIIb progeny and duplication of the pIIa progeny, with the resultant double bristle (twinning) phenotype. This phenotype is similar to that of Notch gain-of-function mutants. Interestingly, the phenotypic change occurred despite asymmetric distribution of Numb, which raises the question of how Notch signaling is induced in this cell.