Early Flexure Formation (~5 weeks post-conception)

• Mesencephalic Flexure
  • Forms at the midbrain-hindbrain (MHB) junction.
• Pontine Flexure
  • Widens the neural tube dorsally.
  • Thins the dorsal hindbrain, defining the roof of the future fourth ventricle.

Developmental Stages of the Cerebellum

• Three overlapping stages:
  • Patterning of cerebellar anlagen territory.
  • Formation of fourth ventricular roof structures.
  • Neuronal proliferation and migration leading to cerebellar hemispheres and vermis formation.

Patterning of Midbrain-Hindbrain Junction (MHB)

• Crucial step defining posterior fossa structures.
• Isthmic organizer (IsO) precisely positioned at MHB junction.
• Interface between two transcription factors:
  • Otx2 (caudal midbrain)
  • Gbx2 (rostral hindbrain)
• Mutual inhibition:
  • Otx2 promotes midbrain tectum formation.
  • Gbx2 promotes cerebellum formation.
• Disturbance in Otx2/Gbx2 balance:
  • Rostro-caudal patterning disorders.
  • Shift in the MHB position.

Role of Fibroblast Growth Factors (FGFs)

• FGF8 secreted by the IsO:
  • Essential for midbrain and cerebellar differentiation.
  • Two variants:
    • Fgf8a: Midbrain tectum development.
    • Fgf8b: Cerebellar development (vermis especially).
• Aberrant FGF signaling disrupts cerebellar roof plate, causing vermis anomalies.

Origin of Cerebellar Structures

• Rhombencephalon consists of eight segments (rhombomeres).
• Cerebellum originates primarily from:
  • R1 alar plate and R1/R2 roof plates: cerebellar vermis.
  • R2 alar plate: cerebellar hemispheres.

Development of Fourth Ventricular Roof

• Critical signaling interactions:
  • Overlying mesenchyme signals neuroepithelium differentiation.
  • Leptomeningeal signaling vital for roof integrity.
• Gene involvement (Foxc1):
  • Expressed in mesenchyme only.
  • Mutations associated with:
    • Cerebellar hypoplasia
    • Mega cisterna magna
    • Dandy-Walker malformation (DWM)
• Association with neurocutaneous syndromes (e.g., PHACES syndrome):
  • Posterior fossa anomalies, hemangioma, arterial anomalies, cardiac defects, eye anomalies, sternal cleft.

Formation of Fourth Ventricle Roof and its Clinical Relevance

• Pontine flexure:
  • Creates diamond-shaped fourth ventricular roof.
  • Plica choroidea (10 weeks p/c):
    • Divides roof into anterior membranous area (AMA) and posterior membranous area (PMA).
    • AMA → future vermis incorporation; contains neurons.
    • PMA → no neurons, primarily ependyma.
• Clinical implications:
  • AMA-derived anomalies (DWM, vermian hypoplasia) associated with developmental impairment.
  • PMA-derived anomalies (Blake’s pouch cyst, mega cisterna magna) generally normal neurodevelopment.

Perforation of Fourth Ventricle Roof

• Begins at 9–10 weeks p/c:
  • Formation and perforation of Blake’s pouch → Foramen of Magendie.
  • Foramina of Luschka open between 14–17 weeks (sometimes as late as 26 weeks or not at all in ~20% of individuals).

Cerebellar Hemispheres and Vermis Development

• Complex stages of proliferation, migration, and differentiation:

1. Neuronal Proliferation Sites

• Two major zones:
  1. Primary Neuroproliferative Zone (7–8 weeks p/c):
     • R1 alar plate, periventricular neuroepithelium.
     • Produces inhibitory (GABAergic) neurons:
       • Purkinje cells, deep cerebellar nuclei.
       • Marker: Ptf1a
  2. Secondary Neuroproliferative Zone (end of third month):
     • Rhombic lips (dorsolateral fourth ventricle).
     • Produces excitatory (glutamatergic) neurons:
       • Marker: Atoh1

2. Migration Pathways

• From rhombic lips:
  • Caudal migration → pre-cerebellar nuclei (pontine, inferior olivary).
  • Subpial migration → External Granular Layer (EGL):
    • Transient highly proliferative superficial layer.
    • Granule cells subsequently migrate inward across Purkinje cell layer forming mature internal granular layer (guided by Bergman glial fibers).
    • EGL involutes postnatally through inward migration and apoptosis.

Vermian Development and Clinical Importance

• Initially delayed compared to hemispheres; accelerates around third month gestation.
• Single cerebellar anlage origin (no hemisphere fusion required).
• Growth proceeds from midbrain-hindbrain junction caudally.
• Usually complete by 18 weeks (sometimes up to 24 weeks).
• Primary fissure separating anterior/posterior lobes visible at ~18 weeks.
• Late development primarily involves the neovermis (just caudal to primary fissure):
  • Important to assess vermian growth accurately, as initial vermian hypoplasia may improve with time.

Clinical vermian evaluation:

• Use specific fetal imaging charts (Imamoglu et al., 2013).
• Normal fastigium-declive line divides vermis into anterior:posterior lobes = 1:2 ratio.
• Typical vermian fissures and lobules fully visible by 27–28 weeks.

Genetic and Molecular Influences

• Gene expression (Foxc1, Atoh1) critical for normal cerebellar development.
• Foxc1 deficiency:
  • Abnormal Atoh1 expression, resulting in vermian hypoplasia and abnormal foliation.
  • Contributes significantly to Dandy-Walker malformation (DWM), mega cisterna magna.

Key Clinical Points

• Posterior fossa developmental anomalies:
  • Frequently due to disruptions in early genetic patterning and mesenchymal-neuroepithelial interactions.
  • Vermian development critical for neurodevelopmental prognosis.
  • AMA vs. PMA origin predicts severity of clinical outcome.