PI3K-AKT-mTOR Cortical Overgrowth Module

Neuroscience Developmental biology Module pi3k_akt_mtor_cortical_overgrowth 1 disorder Pathograph 5

A conserved cortical-overgrowth module representing the shared pathomechanism of malformations of cortical development (MCDs) driven by constitutive activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR growth pathway. Gain-of-function variants in PIK3CA, PIK3R2, AKT3, MTOR, or CCND2 - frequently arising as post-zygotic somatic (mosaic) events restricted to the developing brain - hyperactivate PI3K-AKT-mTOR signaling in neural progenitors. The resulting progenitor hyperproliferation and cell-cycle dysregulation drive cortical overgrowth (megalencephaly, hemimegalencephaly) together with impaired neuronal migration and dyslamination (polymicrogyria, focal cortical dysplasia), producing an epileptogenic cortical substrate and intractable seizures. The same pathway branch recurs across several disease entities and somatic-mosaic lesion types (hemimegalencephaly, focal cortical dysplasia type II, the megalencephaly-capillary malformation [MCAP] and megalencephaly-polymicrogyria-polydactyly-hydrocephalus [MPPH] spectrum, and the PIK3CA-related overgrowth spectrum such as CLOVES), so it is modeled as a module rather than a single disease entry. Conforming disorder nodes substitute the disorder-specific activating lesion (e.g., somatic PIK3CA in hemimegalencephaly/CLOVES, germline or postzygotic PIK3R2/AKT3 in the MCAP/MPPH spectrum, somatic MTOR in focal cortical dysplasia type II, CCND2 stabilization in MPPH) while preserving the conserved hyperactivation-to-overgrowth-to-epilepsy skeleton.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

PI3K-AKT Signal Transduction GO:0043491 ↑ INCREASED TOR Signaling GO:0031929 ↑ INCREASED Neural Progenitor Proliferation GO:0008283 ↑ INCREASED Cerebral Cortex Development GO:0021987 ⚠ ABNORMAL Neuronal Migration GO:0001764 ⚠ ABNORMAL

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "pi3k_akt_mtor_cortical_overgrowth#PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors"). Conforming nodes should substitute the disorder-specific activating lesion: somatic mosaic PIK3CA (hemimegalencephaly, CLOVES/PROS), germline or postzygotic PIK3R2 or AKT3 (MCAP/MPPH megalencephaly spectrum), brain somatic MTOR (focal cortical dysplasia type II), or CCND2 stabilization (MPPH). Existing dismech entries CLOVES_Syndrome.yaml and Tuberous_Sclerosis_Complex.yaml model upstream/parallel arms of this pathway and could add conforms_to references to the "PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors" node; TSC reaches the same mTORC1 hyperactivation node through TSC1/TSC2 loss rather than a PI3K-activating variant. A non-cell-autonomous AKT3-FOXG1-Reelin branch (restricted AKT3-mutant progenitors misexpressing Reelin and misrouting neighboring wild-type neurons; Romero et al. 2018 review sections 2.2.1.8/2.2.8) is a candidate additional node shared with the Reelin lamination module (epic #4098), but is deferred here pending verification of its primary sources and is intentionally not asserted without quotable primary-paper evidence.

Discussions and Knowledge Gaps

In the majority of focal cortical dysplasia type II, hemimegalencephaly, and related PI3K-AKT-mTOR cortical-overgrowth lesions where no activating variant is found, is the causal lesion an undetected low-variant-allele-fraction brain somatic mosaic variant (below the sensitivity of blood/saliva or standard-depth sequencing), a somatic variant in an untested pathway component or non-coding regulatory element, or a mechanistically distinct non-mTOR cause?

KNOWLEDGE GAP OPEN gap_mtor_mcd_undetected_brain_somatic_mosaicism

Attached to: PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors Progenitor Hyperproliferation and Cell-Cycle Dysregulation

This module's trigger node is defined by post-zygotic somatic (mosaic) activating variants confined to the developing brain. That definition carries an unresolved diagnostic-yield gap: in the flagship FCDII cohort, brain somatic MTOR mutations were recovered only by deep whole-exome and amplicon sequencing of resected brain tissue paired with blood, and even then accounted for only 15.6% of subjects studied. The remaining ~84% are not evidence that the module skeleton does not apply to them, but neither can the module assert that it does. Curators conforming a disorder node to this module should therefore not claim complete genetic characterization of the lesion class, and should note whether the cited study sequenced resected brain tissue (rather than blood or saliva alone) and whether non-coding/regulatory space was searched.

Which parts of the PI3K-AKT-mTOR cortical-overgrowth skeleton - mosaic progenitor hyperproliferation, gyral overgrowth, dyslamination, and epileptogenesis - are adequately modeled by rodent in utero electroporation and conditional-mutant approaches, and which require human iPSC-derived cortical organoids or resected human lesion tissue because they depend on outer radial glia and the expanded outer subventricular zone that lissencephalic rodents largely lack?

HUMAN MODEL MISMATCH OPEN gap_mtor_cortical_overgrowth_human_model_translatability

Attached to: Progenitor Hyperproliferation and Cell-Cycle Dysregulation Cortical Overgrowth Impaired Neuronal Migration and Cortical Lamination

The strongest causal demonstrations for this module are focal mosaic expression of mutant MTOR by in utero electroporation in mice, which reproduces migration disruption, cytomegalic neurons, and spontaneous seizures. But the human phenotypes this module models are gyral - megalencephaly, hemimegalencephaly, and polymicrogyria - and the progenitor compartment most plausibly amplifying a mosaic clone into a hemisphere-scale overgrowth is the outer radial glia / expanded outer subventricular zone, which is largely absent from lissencephalic rodents. Mouse models can therefore establish that pathway hyperactivation is sufficient for dyslamination and epileptogenesis while remaining unable to test the overgrowth scaling and gyral-pattern arms. Conforming disorder nodes should keep MODEL_ORGANISM evidence for this module explicitly distinguished from human lesion-tissue and iPSC/organoid evidence.

Proposed experiments: Mosaic PI3K-AKT-mTOR human cortical-organoid overgrowth panel

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Module Collections

Mechanisms of the Epilepsies as mTOR-pathway malformation of cortical development

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Used By Disorder Entries

Focal Cortical Dysplasia Type II via Constitutive mTORC1 Signalling in a Clonal Cortical Patch → PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors , Disrupted Neuronal Migration and Cortical Lamination → Impaired Neuronal Migration and Cortical Lamination , Intrinsically Epileptogenic Dysplastic Cortex → Epileptogenic Cortical Dysplasia and Seizures

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors

trigger

The conserved initiating lesion is constitutive activation of the PI3K-AKT-mTOR growth-signaling cascade in neural progenitor cells. Activating variants in three core components of the PI3K-AKT pathway - PIK3CA (p110-alpha catalytic subunit), PIK3R2 (p85-beta regulatory subunit), and AKT3 - or in the downstream kinase MTOR drive ligand-independent signaling. These variants are frequently post-zygotic somatic (mosaic) events confined to the developing brain, producing mosaic hyperactivation in a clone of progenitors and their progeny.

radial glial cell CL:0000681

PI3K-AKT Signal Transduction GO:0043491 ↑ INCREASED TOR Signaling GO:0031929 ↑ INCREASED

Used by disorders

Focal Cortical Dysplasia Type II as Constitutive mTORC1 Signalling in a Clonal Cortical Patch

Downstream

Progenitor Hyperproliferation and Cell-Cycle Dysregulation Constitutive PI3K-AKT-mTOR signaling drives excess progenitor proliferation and delayed cell-cycle exit.

Show evidence (4 references)

PMID:22729223 SUPPORT Human Clinical

"Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes."

Demonstrates that brain-restricted somatic mutations in PIK3CA, AKT3, and MTOR are recurrent drivers of a cortical overgrowth malformation (hemimegalencephaly), establishing PI3K-AKT-mTOR as the conserved initiating lesion of this module.

PMID:22729223 SUPPORT Human Clinical

"Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling."

States the gain-of-function, mosaic nature of PI3K-AKT3-mTOR activation as the cause of the malformation, the defining feature of the trigger node.

PMID:22729224 SUPPORT Human Clinical

"We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway."

Independently identifies AKT3, PIK3R2, and PIK3CA variants in the megalencephaly (MCAP/MPPH) spectrum, confirming the same pathway branch drives a related overgrowth phenotype and supporting the lumping rationale for this module.

+ 1 more reference

Progenitor Hyperproliferation and Cell-Cycle Dysregulation

amplifier

Hyperactive PI3K-AKT-mTOR signaling increases biosynthesis, cell growth, and proliferation of neural progenitors while dysregulating cell-cycle control. Stabilization of cyclin D2 (CCND2) - normally targeted for proteasomal degradation downstream of GSK-3-beta, which is inhibited by AKT - links the pathway to G1/S cell-cycle progression and expands the progenitor pool, increasing the neuronal output that is subsequently malpositioned.

radial glial cell CL:0000681

Neural Progenitor Proliferation GO:0008283 ↑ INCREASED

Downstream

Cortical Overgrowth Expansion of the progenitor pool and increased cell growth enlarge cortical tissue volume.
Impaired Neuronal Migration and Cortical Lamination Excess and abnormally specified neurons fail to migrate and laminate normally, producing dyslamination.

Show evidence (2 references)

PMID:24705253 SUPPORT In Vitro

"Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2."

Shows the molecular basis by which CCND2 variants stabilize cyclin D2 and dysregulate the cell cycle, the proliferative amplifier engaged downstream of PI3K-AKT in this module.

PMID:22500628 SUPPORT Human Clinical

"We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells."

Establishes that the pathway is active in cortical progenitors during neurogenesis, the cell population whose proliferation is amplified by activating AKT3 variants.

Cortical Overgrowth

effector

Progenitor hyperproliferation and increased cell growth enlarge the cortex, producing megalencephaly when diffuse and hemimegalencephaly when the activating mosaic clone is confined to one hemisphere. The degree and distribution of overgrowth track the timing and spatial extent of the somatic-mosaic activating event.

pyramidal neuron CL:0000598

Cerebral Cortex Development GO:0021987 ⚠ ABNORMAL

Downstream

Epileptogenic Cortical Dysplasia and Seizures Overgrown, abnormally organized cortex forms an epileptogenic substrate.

Show evidence (2 references)

PMID:22729224 SUPPORT Human Clinical

"Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features."

Characterizes the megalencephaly (enlarged brain) overgrowth phenotype produced by PI3K-AKT pathway activation in the MCAP/MPPH spectrum.

PMID:22500628 SUPPORT Human Clinical

"Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection."

Defines the hemimegalencephaly overgrowth phenotype - the lateralized form of cortical overgrowth produced when the activating mosaic clone is confined to one hemisphere - and links it to the epileptogenic outcome of this module.

Impaired Neuronal Migration and Cortical Lamination

effector

Beyond overgrowth, PI3K-AKT-mTOR hyperactivation perturbs radial neuronal migration and inside-out cortical lamination, yielding dyslamination and a polymicrogyria-like or focal cortical dysplasia cortical architecture. The migration defect is mechanistically separable from the proliferative overgrowth and contributes the malformed (as opposed to merely enlarged) component of the phenotype.

migrating cortical neuron CL:0000540

Neuronal Migration GO:0001764 ⚠ ABNORMAL

Used by disorders

Focal Cortical Dysplasia Type II as Disrupted Neuronal Migration and Cortical Lamination

Downstream

Epileptogenic Cortical Dysplasia and Seizures Dyslaminated, dysmorphic-neuron-containing cortex is intrinsically epileptogenic.

Show evidence (2 references)

PMID:25799227 SUPPORT Model Organism

"Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons."

Demonstrates causally, in a mouse model, that focal mTOR hyperactivation disrupts neuronal migration (and produces seizures and cytomegalic neurons), directly supporting the migration/lamination-failure step. Classified MODEL_ORGANISM as the migration phenotype is shown by in utero electroporation in mice.

PMID:25799227 SUPPORT Human Clinical

"Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy."

Establishes dyslamination and dysmorphic neurons as the human-disease correlate of the migration/lamination failure modeled in this node.

Epileptogenic Cortical Dysplasia and Seizures

outcome

The overgrown, dyslaminated cortex containing cytomegalic dysmorphic neurons (and, in focal cortical dysplasia type II, balloon cells) forms an epileptogenic substrate that generates medically refractory seizures. Persistent mTOR hyperactivation in these abnormal neurons shifts the cortical network toward excitation, and the seizures are frequently intractable to antiseizure medication but responsive to mTOR inhibition, identifying the pathway as a treatment target. This terminal step conforms to the conserved epilepsy excitation-inhibition imbalance module, with the mTOR-pathway cortical malformation as the disorder-specific driver of the imbalance.

dysmorphic cytomegalic neuron CL:0000540

TOR Signaling GO:0031929 ↑ INCREASED

Used by disorders

Focal Cortical Dysplasia Type II as Intrinsically Epileptogenic Dysplastic Cortex

Show evidence (2 references)

PMID:25799227 SUPPORT Human Clinical

"This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD."

Links brain somatic mTOR activation to focal cortical dysplasia with intractable epilepsy and names mTOR as the actionable treatment target, supporting the epileptogenic outcome and its therapeutic vulnerability.

PMID:25799227 SUPPORT Model Organism

"Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures."

Shows in the mouse model that mTOR inhibition reverses both the cellular abnormality and the seizures, confirming mTOR hyperactivation as the proximate driver of the epileptogenic phenotype. Classified MODEL_ORGANISM because the rescue is demonstrated in mice.