This is a mechanism module, not a broad "microcephaly" or "MCD" disease entry. Disorder entries should use conforms_to only when the dominant pathograph involves radial-glial or neural-progenitor division, spindle, centrosome, cell-cycle, fate, or apoptosis defects. Do not use this as the primary skeleton for isolated postmitotic neuronal migration failure, apical-neuroependyma integrity failure, pial-basement-membrane overmigration, Reelin terminal-translocation defects, interneuron migration/specification defects, or PI3K-AKT-mTOR overgrowth unless the conforming entry has an explicit progenitor branch. Some genes, especially PAFAH1B1/LIS1, NDE1/NDEL1, WDR62, and tubulin/motor genes, can affect both progenitors and migrating neurons; use this module for the progenitor branch and the microtubule migration module for the postmitotic neuronal migration branch. Programmed cell-death mechanisms must preserve directionality: CRADD/TLIS is a reduced apoptosis branch with megalencephaly/thin lissencephaly, whereas ZIKV and some spindle defects can increase cell death or premature differentiation and deplete progenitors.
Neural Progenitor Centrosome-Spindle Dysfunction Model
progenitor_centrosome_spindle_model
CANONICAL
Evidence: 2
Evidence balance
2 support
Centrosome and mitotic spindle proteins coordinate radial-glial and neural-progenitor mitosis, cleavage orientation, symmetric versus asymmetric division, and cell-cycle progression. Pathogenic variants, chromosomal deletions, or viral cytopathy can disrupt this apparatus or the coupled programmed-cell-death machinery. The resulting progenitor-pool distortion changes neuronal output and cortical architecture, producing small cortex, simplified gyration, microlissencephaly, pachygyria, polymicrogyria-like malformations, or, for reduced-apoptosis branches, megalencephaly with thin lissencephaly.
Which progenitor defects detected in mouse or invertebrate models are conserved in human radial-glial, outer-radial-glial, and organoid systems, and which require human-specific OSVZ or oRG biology?
HUMAN MODEL MISMATCH
OPEN
gap_progenitor_human_model_translatability
Attached to:
Abnormal Progenitor Division and Fate Choice
Progenitor Pool Distortion
The seed review emphasized that organoids and iPSC-derived cortical models are especially important for progenitor mechanisms because human OSVZ/oRG biology is not fully represented in lissencephalic rodents. For curation, mouse or invertebrate spindle evidence should establish conserved proximal mechanisms, but human organoids, fetal tissue, or isogenic iPSC systems may be needed to decide whether a disease entry has an oRG-specific branch.
Proposed experiments:
Isogenic cortical-organoid progenitor fate and spindle panel
Centrosome and Mitotic Spindle Perturbation
trigger
Genetic, chromosomal, or viral perturbations disrupt the centrosome, centriole, mitotic spindle, or microtubule-severing apparatus used by neural progenitors and radial glia. Representative mechanisms include NDE1 centrosome/spindle defects, LIS1-NDEL1-dynein spindle orientation defects, WDR62 spindle-pole localization defects, ASPM spindle microtubule assembly defects, and KATNB1/katanin-dependent microtubule remodeling defects.
Downstream
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Abnormal Progenitor Division and Fate Choice
Abnormal Progenitor Division and Fate Choice
central effector
Centrosome/spindle perturbation alters radial-glial and neural-progenitor mitotic progression, cleavage orientation, symmetric versus asymmetric division, and fate specification. Depending on the gene and developmental context, this can reduce progenitor self-renewal, cause premature neuronal differentiation, or delay/arrest the cell cycle.
Downstream
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Progenitor Pool Distortion
Progenitor Pool Distortion
effector
Abnormal division, fate choice, cell-cycle progression, or apoptosis changes the size, position, and composition of the cortical progenitor pool. The common state is not always simple depletion: some branches cause premature differentiation or cell death, some mislocalize progenitors, and reduced apoptosis can produce megalencephaly or excessive/inappropriate cell survival.
Downstream
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Abnormal Cortical Neuron Output and Gyration
Programmed Cell Death Imbalance Branch
amplifier
Some cortical malformations arise because programmed cell death is misregulated rather than because progenitors are simply depleted. CRADD loss reduces caspase-2-mediated apoptosis and is associated with megalencephaly with thin lissencephaly, whereas viral or mitotic-stress branches can increase cell death and reduce the progenitor pool.
Downstream
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Progenitor Pool Distortion
Viral Progenitor Cytopathy Branch
trigger
Viral infection can phenocopy parts of the genetic progenitor centrosome-spindle module by targeting proliferating neural progenitors, disrupting centrosomes or mitosis, inducing premature differentiation or cell death, and reducing cortical output. This branch should be used for congenital infection entries such as congenital Zika syndrome, not for inherited centrosome disorders.
Downstream
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Progenitor Pool Distortion
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Programmed Cell Death Imbalance Branch
Abnormal Cortical Neuron Output and Gyration
outcome
Progenitor-pool distortion changes the number, timing, and spatial allocation of cortical neurons, producing reduced cortical neuron output, small or overgrown cortex depending on branch direction, simplified gyral pattern, microlissencephaly, pachygyria, polymicrogyria-like malformation, thin lissencephaly, or cortical thinning.