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
Show evidence (4 references)
"In vitro analysis demonstrated that Nde1 is essential for centrosome duplication and mitotic spindle assembly."
Supports NDE1 as a proximal centrosome and spindle mechanism in cortical progenitor development.
"We found that LIS1 is required for the tight control of chromosome congression and segregation to dictate kinetochore-microtubule (MT) interactions and anaphase progression."
Supports the LIS1/NDEL1/dynein branch as a mitotic spindle and chromosome segregation mechanism.
"WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells."
Links WDR62 cortical malformation genetics to the progenitor spindle-pole apparatus.
+ 1 more reference
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
Show evidence (4 references)
"more dramatic defects on mitotic progression, mitotic orientation, and mitotic chromosome localization in cortical progenitors were observed in Nde1 mutant embryos."
Supports the central progenitor-division defect downstream of NDE1 loss.
"WDR62 knockdown leads to premature differentiation of neural progenitor cells (NPCs)."
Supports premature progenitor differentiation as a WDR62-related fate branch.
"In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers."
Supports asymmetric progenitor division, centrosome, spindle, and cell-cycle defects as the KATNB1/katanin branch.
+ 1 more reference
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
Show evidence (3 references)
"These findings support a proliferative defect in brains of patients with WDR62 mutations, potentially affecting the outer SVZ (precursors to upper layer cortical neurons)21 as well as defective neuronal migration"
Human fetal pathology supports progenitor-pool distortion in WDR62 disease.
"We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions."
Human MDS organoids support early neural stem cell apoptosis and altered division as a progenitor-pool mechanism.
"The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning."
ZIKV organoid evidence supports the acquired viral cytopathy branch of progenitor-pool depletion.
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
Show evidence (2 references)
"Megalencephaly and lissencephaly associated with defective programmed cell death from loss of CRADD function in humans implicate reduced apoptosis as an important pathophysiological mechanism of cortical malformation."
Supports a reduced-apoptosis branch distinct from progenitor depletion by increased apoptosis.
"we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death."
Supports the opposite acquired branch where viral mitotic injury increases cell death in neural stem/radial-glial cells.
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
Show evidence (2 references)
"Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors."
Supports selective infection of proliferating apical progenitors in human brain organoids.
"ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis."
Supports mitotic/centrosomal disruption as a viral progenitor cytopathy mechanism.
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.
Show evidence (4 references)
"we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly"
Supports NDE1-related progenitor mechanisms causing severe cortical size and gyration outcomes.
"We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture."
Supports WDR62-associated microcephaly and cortical architecture defects as an outcome of the module.
"Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1"
Supports KATNB1 as a human cortical malformation gene in the module.
+ 1 more reference