Impaired Reelin-Dab1 Signaling Contributes to Neuronal Migration Deficits of Tuberous Sclerosis Complex

Abstract

SUMMARY Tuberous sclerosis complex (TSC) is associated with neurodevelopmental abnormalities, including defects in neuronal migration. However, the alterations in cell signaling mechanisms critical for migration and final positioning of neurons in TSC remain unclear. Our detailed cellular analyses reveal that reduced Tsc2 in newborn neurons causes abnormalities in leading processes of migrating neurons, accompanied by significantly delayed migration. Importantly, we demonstrate that Reelin-Dab1 signaling is aberrantly regulated in TSC mouse models and in cortical tubers from TSC patients owing to enhanced expression of the E3 ubiquitin ligase, Cul5, a known mediator of pDab1 ubiquitination. Likewise, mTORC1 activation by Rheb overexpression generates similar neuronal and Reelin-Dab1 signaling defects, and directly upregulates Cul5 expression. Inhibition of mTORC1 by rapamycin treatment or by reducing Cul5 largely restores normal leading processes and positioning of migrating neurons. Thus, disrupted Reelin-Dab1 signaling is critically involved in the neuronal migration defects of TSC.

Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration

“…Of the many effectors downstream of mTORC1, we identified 4E-BPs as a molecular target that can restore many aspects of normal cortical circuitry. Considering that rapamycin does not fully block mTORC1 signaling through 4E-BPs in vitro (14), our report that normalizing signaling through 4E-BPs, but not S6Ks, prevents Rheb CA -induced mislamination seems to conflict with studies showing that rapamycin can rescue many phenotypes, including mislamination, in TSC models (5,7,49). However, the effects of rapamycin on translation and 4E-BP signaling after chronic administration in vivo are not well studied, particularly in the brain.…”

“…The high incidence of negative outcomes in individuals with such malformations (2), which are often associated with intractable childhood seizures, underscores the need to better understand the molecular etiology of these developmental lesions. Animal models have demonstrated the causative effect of increased mTORC1 signaling on mislamination (3)(4)(5)(6)(7). The pharmacological mTORC1 blocker rapamycin has also been shown to reverse some of the developmental abnormalities and associated seizure activity in several of these mouse models (5,6,(8)(9)(10), further emphasizing the importance of mTORC1 in the disease pathogenesis.…”

The mTOR signalling cascade: paving new roads to cure neurological disease

“…Indeed, in mouse models of TSC, full knockout of either gene is needed to cause altered brain morphology and mTOR activation 42 . Recent evidence suggests that TSC2 mutations affect neuronal migration through interactions with the reelin pathway 43 .…”

Rheb in neuronal degeneration, regeneration, and connectivity

“…In addition, constitutive activation of Rheb in the NPCs also affects neuroblast migration, probably due to its role in Reelin-Dab signaling (Moon et al, 2015). Taken together, Rheb is essential for the differentiation of NPCs, although its aberrant activation may cause abnormal differentiation.…”

“…Constitutive activation of Rheb, in the NPCs and neuroblasts of subventricular zone in mouse may lead to premature neuronal differentiation and disruption in cell migration either though obstruction of the migratory path and/or release of aberrant cues (Lafourcade et al, 2013). In TSC neurons, neuronal migration defects were induced by upregulation of Cul5 expression by the hyperactivated mTORC1, leading to disruption of Reelin-Dab1 signaling (Moon et al, 2015).…”