This is a mechanism module, not a disease entry and not a generic "lissencephaly" bucket. Disorder entries should conform to this module only when the core pathograph is Reelin pathway control of terminal somal translocation and cortical lamination. Primary RELN and VLDLR disease entries can map to the core ligand/receptor skeleton. Disease-specific entries with PI3K-AKT-mTOR activation should use this module only for a secondary AKT3-FOXG1-Reelin misexpression branch, and should otherwise conform to an overgrowth/mTOR module if that is the dominant skeleton. Do not use this as the primary skeleton for microtubule-dependent neuronal migration arrest, neural progenitor centrosome-spindle failure, apical neuroependyma integrity failure, pial basement-membrane/radial-glial endfoot failure, or interneuronopathy.
Reelin Terminal Translocation and Lamination Model
reelin_terminal_translocation_model
CANONICAL
Evidence: 3
Evidence balance
3 support
Reelin secreted by Cajal-Retzius cells in the marginal zone binds VLDLR and ApoER2/LRP8 on migrating neurons, activating DAB1 and downstream adhesion and cytoskeletal effectors. Failure of this signal impairs glia-independent somal translocation and leading-process stabilization, so late and early cortical neurons fail to settle in the proper inside-out order. The same pathway also organizes hippocampal and cerebellar development, explaining the recurring association of cortical lamination defects with hippocampal and cerebellar hypoplasia or disorganization.
Which parts of the RELN/VLDLR/LRP8/DAB1 terminal-translocation mechanism are adequately captured by mouse reeler and pathway-mutant models, and which require human iPSC-derived cortical organoids or organotypic human cortical assays to resolve human-specific progenitor, lamination, seizure, hippocampal, or cerebellar branches?
HUMAN MODEL MISMATCH
OPEN
gap_reelin_human_model_translatability
Attached to:
Cajal-Retzius Reelin Ligand Deficiency
VLDLR-ApoER2-DAB1 Signal Transduction Failure
Terminal Somal Translocation Failure
AKT3-FOXG1 Secondary Reelin Misexpression Branch
The seed review treats Reelin as one of the better conserved mouse-human MCD mechanisms, but it also emphasizes model-system limitations across cortical malformation curation. This should be represented as a human/model mismatch knowledge gap: mouse reeler, Vldlr/Apoer2, Dab1, ephrin-B, and Clasp2 models can establish the core terminal-translocation mechanism, but human iPSC-derived cortical organoids or organotypic human-tissue assays may be needed to test outer-radial-glia context, human-specific timing, seizure-relevant circuitry, and whether AKT3-FOXG1-driven Reelin misexpression follows the same branch.
Proposed experiments:
Isogenic Reelin-pathway cortical-organoid terminal-translocation panel
Cajal-Retzius Reelin Ligand Deficiency
trigger
Pathogenic RELN variants reduce or alter the secreted Reelin cue normally produced by Cajal-Retzius cells in the developing cortical marginal zone. Loss of this ligand deprives postmitotic neurons of the extracellular positioning signal required for terminal translocation and inside-out lamination.
Downstream
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VLDLR-ApoER2-DAB1 Signal Transduction Failure
VLDLR-ApoER2-DAB1 Signal Transduction Failure
central effector
Reelin normally binds VLDLR and ApoER2/LRP8 on migrating neurons, causing DAB1 activation through Src-family kinase signaling. Pathogenic VLDLR loss, RELN receptor-binding defects, or impaired DAB1 pathway propagation reduce the signal that couples the extracellular Reelin cue to neuron-intrinsic migration and lamination effectors.
Downstream
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Rap1-Cadherin Leading Process Instability
-
Ephrin-B and CLASP2 Reelin Effector Branch
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Hippocampal and Cerebellar Organization Defect
Rap1-Cadherin Leading Process Instability
effector
Impaired DAB1 signaling reduces Rap1-dependent regulation of cadherin adhesion, destabilizing the leading processes of translocating cortical neurons. This node captures the neuron-intrinsic effector step that links the Reelin receptor-adaptor signal to terminal somal translocation.
Downstream
-
Terminal Somal Translocation Failure
Ephrin-B and CLASP2 Reelin Effector Branch
amplifier
Ephrin-B proteins and CLASP2 represent Reelin-associated effector or modulator branches that influence DAB1 phosphorylation, cytoskeletal dynamics, neurite extension, motility, and neuronal positioning. This is a branch off the core pathway rather than a separate disease skeleton unless a disorder-specific entry demonstrates primary disruption of this branch.
Downstream
-
Terminal Somal Translocation Failure
Terminal Somal Translocation Failure
central effector
Developing cortical neurons fail to complete the glia-independent terminal somal translocation step, often retracting or destabilizing leading processes after contact with the marginal zone. This failure is the central cellular mechanism distinguishing this module from earlier locomotion or microtubule-based migration arrest modules.
Downstream
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Cortical Lamination and Gyral Simplification
Cortical Lamination and Gyral Simplification
consequence
Failed terminal translocation and Reelin-pathway signaling produce disrupted inside-out lamination, simplified gyral patterning, pachygyria or lissencephaly-like cortical malformation depending on disease context and severity. Disease entries should instantiate the specific imaging or histopathologic endpoint rather than treating this module endpoint as a single disease.
Hippocampal and Cerebellar Organization Defect
consequence
Reelin-pathway disruption affects laminated structures beyond neocortex, especially hippocampal formation and cerebellum. Human RELN/VLDLR disease and mouse Reln/Vldlr/ApoER2 pathway models show recurring hippocampal and cerebellar abnormalities, while RELN receptor-binding hypomorphs can uncouple cortical/hippocampal defects from cerebellar hypoplasia.
AKT3-FOXG1 Secondary Reelin Misexpression Branch
amplifier
In focal cortical malformations driven by mosaic AKT3 activation, Reelin can be misexpressed through FOXG1-dependent derepression in neural progenitors. This produces a non-cell-autonomous migration defect in neighboring cells. The branch should be curated as secondary Reelin-pathway involvement within a PI3K-AKT-mTOR disease skeleton unless Reelin misexpression is the central causal mechanism of the entry.
Downstream
-
Terminal Somal Translocation Failure