Microtubule-Dependent Neuronal Migration Failure Module

Module microtubule_dependent_neuronal_migration_failure 9 disorders Pathograph 5

Conserved cortical malformation mechanism in which pathogenic variants in microtubule-associated proteins, tubulin subunits, gamma-tubulin nucleation machinery, dynein, or kinesin motors perturb microtubule dynamics and microtubule-based movement in developing neurons. The shared skeleton is microtubule apparatus perturbation followed by defective neuronal nucleokinesis/radial migration and cortical dyslamination or neuronal ectopia. This module is intended for lissencephaly, subcortical band heterotopia, and selected polymicrogyria-like malformations where microtubule-dependent neuronal migration is central.

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Pathophysiology Nodes

4 shared nodes are defined in this module.

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Cell Types

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Biological Processes

Notes

This is a mechanism module, not a disease or a broad "tubulinopathy" lump. Disorder entries should use conforms_to only when the core pathograph is microtubule-dependent neuronal motility or migration failure. Conforming disease entries may substitute the specific gene and mechanism, such as PAFAH1B1/LIS1 dosage-sensitive dynein regulation, DCX microtubule stabilization, TUBA1A or TUBB2B heterodimer/MAP-binding disruption, TUBG1 nucleation defects, or DYNC1H1/KIF motor dysfunction. Do not use this module as the primary skeleton when the dominant mechanism is neural progenitor depletion/spindle failure, apical neuroependyma integrity failure, pial basement-membrane/radial-glial endfoot failure, Reelin terminal-translocation signaling, ARX interneuronopathy, or PI3K-AKT-mTOR overgrowth; those should use separate modules or subtype branches. TUBB3-related disease may conform only for its microtubule/axon-guidance branch if cortical migration is not the primary demonstrated defect.

Discussions and Knowledge Gaps

Which microtubule-dependent migration defects are conserved across mouse in utero perturbation/knockout models, biochemical or cultured-cell assays, and human iPSC-derived cortical organoids, and which require human-specific progenitors such as outer radial glia?

HUMAN MODEL MISMATCH OPEN gap_microtubule_human_model_translatability

Attached to: Microtubule Apparatus Perturbation Microtubule-Based Neuronal Motility Failure

The seed review emphasized rodent-versus-human cortical-development differences and the value of iPSC/organoid systems. For curation this should be treated as a human/model mismatch knowledge-gap category: mouse migration evidence can establish conserved mechanisms, but organoids or fetal-human data may be needed to decide whether outer-radial-glia timing, cleavage orientation, or human-specific transcript usage changes the pathograph for a specific disorder.

Proposed experiments: Isogenic cortical-organoid migration rescue panel

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Used By Disorder Entries

KATNB1-related Cortical Malformation via Microtubule-Dependent Neurogenesis and Neuronal Migration Failure → Microtubule-Based Neuronal Motility Failure , Reduced Cortical Output and Microlissencephaly → Cortical Dyslamination and Neuronal Ectopia

Lissencephaly Spectrum Disorders via Cytoskeletal and Microtubule Dysfunction → Microtubule Apparatus Perturbation , LIS1-NUDEL-Dynein Nucleokinesis Failure → Microtubule-Based Neuronal Motility Failure , DCX Microtubule Stabilization Failure → Microtubule Apparatus Perturbation

Miller-Dieker Lissencephaly Syndrome via LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction → Microtubule-Based Neuronal Motility Failure

NDE1-related Microcephaly-Lissencephaly via Dynein-Dependent Neuronal Migration Failure → Microtubule-Based Neuronal Motility Failure , Cortical Dyslamination and Lissencephaly → Cortical Dyslamination and Neuronal Ectopia

SRPX2-related Speech-Epilepsy-Polymicrogyria via Tubulin Acetylation and Neuronal Migration Defect → Microtubule-Based Neuronal Motility Failure , Perisylvian Cortical Organization Failure → Cortical Dyslamination and Neuronal Ectopia

TUBA1A-related Tubulinopathy via Altered Alpha-Tubulin (TUBA1A) Function → Microtubule Apparatus Perturbation , Impaired Microtubule-Dependent Neuronal Migration → Microtubule-Based Neuronal Motility Failure , Cortical Dyslamination and Lissencephaly Spectrum → Cortical Dyslamination and Neuronal Ectopia

TUBB/TUBB5-related Microcephaly via Altered TUBB/TUBB5 Beta-Tubulin Function → Microtubule Apparatus Perturbation , Impaired Neurogenic Division and Migration → Microtubule-Based Neuronal Motility Failure

TUBB2A/TUBB2B-related Cortical Malformation via Altered Beta-Tubulin (TUBB2A/TUBB2B) Function → Microtubule Apparatus Perturbation , Impaired Microtubule-Dependent Neuronal Migration and Organization → Microtubule-Based Neuronal Motility Failure , Polymicrogyria-like Cortical Dysplasia and Extracortical Tubulinopathy Pattern → Cortical Dyslamination and Neuronal Ectopia

TUBB3-related Tubulinopathy via Altered Beta-III Tubulin (TUBB3) Function → Microtubule Apparatus Perturbation , Impaired Kinesin-Microtubule Interaction and Axon Guidance Failure → Axon Guidance and Projection Wiring Defects , Impaired Microtubule-Dependent Neuronal Migration → Microtubule-Based Neuronal Motility Failure , Cortical Dyslamination and Pontocerebellar Malformation → Cortical Dyslamination and Neuronal Ectopia

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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

Microtubule Apparatus Perturbation

trigger

Pathogenic variation perturbs the microtubule apparatus used by developing neurons and neural progenitors. Representative mechanisms include defective DCX-mediated microtubule stabilization, impaired alpha/beta-tubulin heterodimer formation or MAP binding, gamma-tubulin nucleation defects, altered dynein microtubule binding, and kinesin ATPase/folding defects.

migrating cortical neuron CL:0000540 radial glial cell CL:0000681

microtubule cytoskeleton organization GO:0000226 DYSREGULATED microtubule-based process GO:0007017 DYSREGULATED

Used by disorders

Lissencephaly Spectrum Disorders as Cytoskeletal and Microtubule Dysfunction

Lissencephaly Spectrum Disorders as DCX Microtubule Stabilization Failure

TUBA1A-related Tubulinopathy as Altered Alpha-Tubulin (TUBA1A) Function

TUBB/TUBB5-related Microcephaly as Altered TUBB/TUBB5 Beta-Tubulin Function

TUBB2A/TUBB2B-related Cortical Malformation as Altered Beta-Tubulin (TUBB2A/TUBB2B) Function

TUBB3-related Tubulinopathy as Altered Beta-III Tubulin (TUBB3) Function

Downstream

Microtubule-Based Neuronal Motility Failure Defective microtubule dynamics, MAP binding, and motor function impair the centrosome-nucleus coupling and cytoskeletal remodeling required for radial neuronal migration.
Axon Guidance and Projection Wiring Defects Some tubulin variants, especially TUBB3 variants, primarily alter axon guidance or projection maintenance rather than cortical cell migration. This is an optional branch for conforming entries, not the core skeleton.

Microtubule-Based Neuronal Motility Failure

central effector

Migrating neurons fail to execute normal microtubule-dependent movement, including leading-process stabilization, nucleokinesis, centrosome-nucleus coupling, and radial migration along radial-glial scaffolds. Depending on the gene and developmental window, the defect can appear as delayed migration, arrested cells in intermediate/subventricular regions, or abnormal neuronal positioning.

migrating cortical neuron CL:0000540 pyramidal neuron CL:0000598

neuron migration GO:0001764 DECREASED microtubule-based movement GO:0007018 DYSREGULATED

Used by disorders

KATNB1-related Cortical Malformation as Microtubule-Dependent Neurogenesis and Neuronal Migration Failure

Lissencephaly Spectrum Disorders as LIS1-NUDEL-Dynein Nucleokinesis Failure

Miller-Dieker Lissencephaly Syndrome as LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction

NDE1-related Microcephaly-Lissencephaly as Dynein-Dependent Neuronal Migration Failure

SRPX2-related Speech-Epilepsy-Polymicrogyria as Tubulin Acetylation and Neuronal Migration Defect

TUBA1A-related Tubulinopathy as Impaired Microtubule-Dependent Neuronal Migration

TUBB/TUBB5-related Microcephaly as Impaired Neurogenic Division and Migration

TUBB2A/TUBB2B-related Cortical Malformation as Impaired Microtubule-Dependent Neuronal Migration and Organization

TUBB3-related Tubulinopathy as Impaired Microtubule-Dependent Neuronal Migration

Downstream

Cortical Dyslamination and Neuronal Ectopia Failed or delayed neuronal migration prevents appropriate placement of cortical neurons, producing abnormal lamination, heterotopia, or lissencephaly/pachygyria-like cortical organization.

Cortical Dyslamination and Neuronal Ectopia

effector

The tissue-level effect is abnormal cortical architecture: neurons remain ectopic, the cortical plate is thickened or poorly laminated, and gyral patterning may show lissencephaly, pachygyria, subcortical band heterotopia, or selected polymicrogyria-like malformations. Disorder-specific entries should state the relevant anatomic gradient and whether pial basement membrane failure, progenitor depletion, or another module is also needed.

cortical neuron CL:0000540

cerebral cortex development GO:0021987 DYSREGULATED neuron migration GO:0001764 DECREASED

Used by disorders

KATNB1-related Cortical Malformation as Reduced Cortical Output and Microlissencephaly

NDE1-related Microcephaly-Lissencephaly as Cortical Dyslamination and Lissencephaly

SRPX2-related Speech-Epilepsy-Polymicrogyria as Perisylvian Cortical Organization Failure

TUBA1A-related Tubulinopathy as Cortical Dyslamination and Lissencephaly Spectrum

TUBB2A/TUBB2B-related Cortical Malformation as Polymicrogyria-like Cortical Dysplasia and Extracortical Tubulinopathy Pattern

TUBB3-related Tubulinopathy as Cortical Dyslamination and Pontocerebellar Malformation

Axon Guidance and Projection Wiring Defects

amplifier

Optional side branch in which the same microtubule/tubulin apparatus disrupts axon guidance, commissural tract development, or long-range projection maintenance. This branch is important for TUBB3-related phenotypes and some broader tubulin/motor disorders, but its presence should not be assumed for all conforming microtubule-migration entries.

neuron CL:0000540

neuron projection morphogenesis GO:0048812 DYSREGULATED neuron projection guidance GO:0097485 DYSREGULATED

Used by disorders

TUBB3-related Tubulinopathy as Impaired Kinesin-Microtubule Interaction and Axon Guidance Failure