Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion

Feliciano, David M.; Quon, Jennifer L.; Su, Tiffany Y; Taylor, M.L.; Bordey, Angélique

doi:10.1093/hmg/ddr511

Cited by 65 publications

(90 citation statements)

References 45 publications

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“…Figure 1 demonstrates how disruptions in the vast array of developmental processes governed by mTOR signaling in the central nervous system could lead to specific morphologic and physiologic phenotypes that contribute to the development of epilepsy, intellectual and neurocognitive impairment, and other neurological disorders in TSC. 7,10,18-21 63 Zhou et al 66 TSC1 …”

Section: Overview Of Epilepsy In Tscmentioning

confidence: 99%

Mechanistic Target of Rapamycin (mTOR) in Tuberous Sclerosis Complex-Associated Epilepsy

Curatolo

2015

Pediatric Neurology

124

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Section: Overview Of Epilepsy In Tscmentioning

confidence: 99%

Mechanistic Target of Rapamycin (mTOR) in Tuberous Sclerosis Complex-Associated Epilepsy

Curatolo

2015

Pediatric Neurology

124

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“…The major function of the TSC complex is to repress the activity of Ras homolog enriched in brain (Rheb), the canonical activator of mTOR complex 1 (mTORC1). Thus, loss of Tsc1 in neurons results in hyperactive mTORC1 and morphological changes such as increased soma size and dendritic hypertrophy (Feliciano et al, 2011; 2012; 2013a; Meikle et al, 2007; Neuman and Henske, 2011). To identify dysregulated genes that may contribute to dendritic overgrowth in TSC, we performed a PCR array from conditional Tsc1 knockout mouse tissue and found that the filamin A ( Flna ) transcript was significantly elevated.…”

Section: Introductionmentioning

confidence: 99%

MEK-ERK1/2-Dependent FLNA Overexpression Promotes Abnormal Dendritic Patterning in Tuberous Sclerosis Independent of mTOR

Zhang

Bartley

Gong

et al. 2014

Neuron

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Summary Abnormal dendritic complexity is a shared feature of many neurodevelopmental disorders associated with neurological defects. Here, we found that the actin-crosslinking protein filamin A (FLNA) is overexpressed in tuberous sclerosis complex (TSC) mice, a PI3K-mTOR model of neurodevelopmental disease that is associated with abnormal dendritic complexity. Both under-and overexpression of FLNA in wild-type neurons led to more complex dendritic arbors in vivo, suggesting that an optimal level of FLNA expression is required for normal dendritogenesis. In Tsc1null neurons, knocking down FLNA in vivo prevented dendritic abnormalities. Surprisingly, FLNA overexpression in Tsc1null neurons was dependent on MEK1/2 but not mTOR activity despite both pathways being hyperactive. In addition, increasing MEK-ERK1/2 activity led to dendritic abnormalities via FLNA and decreasing MEK-ERK1/2 signaling in Tsc1null neurons rescued dendritic defects. These data demonstrate that altered FLNA expression increases dendritic complexity and contributes to pathologic dendritic patterning in TSC in an mTOR-independent, ERK1/2-dependent manner.

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“…The Pten-deficient phenotype also differs from 3429 RESEARCH ARTICLE Pten function in neuroblasts migration defects caused by mutations in other components of the PI3K pathway. Deletion of Tsc1 in the neonatal SVZ, which also activates mTorc1, but induces different feedback signaling compared with Pten loss, caused a decrease in neuroblast migration speed (Huang and Manning, 2009;Feliciano and Bordey, 2012). Deletion of Erbb4, a receptor tyrosine kinase that has been shown to signal through PI3K as well as other downstream pathways, disrupted proper directional orientation, with a significant decrease in the proportion of neuroblasts migrating towards the OB (Anton et al, 2004).…”

mentioning

confidence: 99%

Pten deletion causes mTorc1-dependent ectopic neuroblast differentiation without causing uniform migration defects

et al. 2012

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SUMMARYNeuronal precursors, generated throughout life in the subventricular zone, migrate through the rostral migratory stream to the olfactory bulb where they differentiate into interneurons. We found that the PI3K-Akt-mTorc1 pathway is selectively inactivated in migrating neuroblasts in the subventricular zone and rostral migratory stream, and activated when these cells reach the olfactory bulb. Postnatal deletion of Pten caused aberrant activation of the PI3K-Akt-mTorc1 pathway and an enlarged subventricular zone and rostral migratory stream. This expansion was caused by premature termination of migration and differentiation of neuroblasts and was rescued by inhibition of mTorc1. This phenotype is reminiscent of lamination defects caused by Pten deletion in developing brain that were previously described as defective migration. However, live imaging in acute slices showed that Pten deletion did not cause a uniform defect in the mechanics of directional neuroblast migration. Instead, a subpopulation of Pten-null neuroblasts showed minimal movement and altered morphology associated with differentiation, whereas the remainder showed unimpeded directional migration towards the olfactory bulb. Therefore, migration defects of Pten-null neurons might be secondary to ectopic differentiation. KEY WORDS: Pten, Differentiation, Migration, Neuroblast, mTOR/PI3K, MousePten deletion causes mTorc1-dependent ectopic neuroblast differentiation without causing uniform migration defects RESEARCH ARTICLEPten function in neuroblasts deletion in this study was a decrease in random movement in the absence of a chemotactic signal (Hoeller and Kay, 2007). Thus, even within simple organisms, the precise mechanisms through which PI3K signaling influences migration are not straightforward.Inherited mutations disrupting PI3K-AKT-mTORC1 regulation are associated with human syndromes that include neurological abnormalities, indicating that the pathway is important in normal neural development and/or function (Inoki et al., 2005;Endersby and Baker, 2008). Conditional knockout mice showed that Pten is important in brain for diverse processes, including proper neuronal positioning during development as well as negative regulation of neural stem cell self-renewal and proliferation, and neuronal morphogenesis and size regulation (Backman et al., 2001;Kwon et al., 2001;Marino et al., 2002;Waite and Eickholt, 2010). However, the underlying mechanism of how Pten is involved in neuronal migration is currently unknown.In the present study, we demonstrated that Pten inhibits downstream activation of mTorc1 in normal migrating neuroblasts in the RMS. Postnatal deletion of Pten in this population resulted in ectopic positioning of neurons that failed to reach their final destination, reminiscent of defects in radial glia-guided neuronal migration caused by Pten deletion during development. The phenotype was fully rescued by rapamycin, demonstrating that mTorc1 is required for the Pten-mediated regulation of migration in the RMS. We used live imaging o...

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Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion

Cited by 65 publications

References 45 publications

Mechanistic Target of Rapamycin (mTOR) in Tuberous Sclerosis Complex-Associated Epilepsy

Mechanistic Target of Rapamycin (mTOR) in Tuberous Sclerosis Complex-Associated Epilepsy

MEK-ERK1/2-Dependent FLNA Overexpression Promotes Abnormal Dendritic Patterning in Tuberous Sclerosis Independent of mTOR

Pten deletion causes mTorc1-dependent ectopic neuroblast differentiation without causing uniform migration defects

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