Cerebellar development and disease

Abstract

The molecular control of cell-type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and nonoverlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation, and pontocerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function, and neuronal cilia in patterning, homeostasis, and cell proliferation during cerebellar development. Together, mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

Figure 1. Overview of mouse cerebellar neurogenesis

(A) Schematic parasagittal section through the mid/hindbrain region of a mouse e12.5 neural tube. The cerebellum is a dorsal derivative of hindbrain rhombomere 1 (rh1) under the influence signaling from both the isthmic organizer and fourth ventricle roof plate. Within the developing cerebellar anlage two distinct progenitor zones form marked by distinct transcription factors, Math1 and Ptf1a. Math1 expression in the rhombic lip (rl) is induced by Bmp signaling from the roof plate (rp) which itself differentiates into the choroid plexus (CPe). Genetic fate mapping studies have shown that Math1+ RL progenitor cells give rise to multiple glutamaterigic+ derivatives in a time-dependent sequence. Early progenitors feed into the rostral migratory stream (RLS). The RLS migrates over the cerebellar anlage and gives rise to multiple brain stem precerebellar nuclei, including the pontine nuclei (pn). RLS cells next give rise to glutamategic deep cerebellar nuclei which settle into the nuclear transitory zone (ntz). Math1+ RL cells also generate cerebellar granule cells (GC) which form the cerebellar external granule layer in an anterior to posterior temporal gradient. Unipolar brush cells (UBCs) are the final Math1+ RL population and migrate through the cerebellar while matter. Concurrently, the ventricular zone (vz) of the cerebellar anlage expresses Ptf1a. These progenitors exit the cell cycle, migrate radially into the cerebellar anlage and give rise to all GABAergic cerebellar cells, including Purkinje cells, GABAergic DCN and cerebellar interneurons including Basket and Stellate cells. m=midbrain; aq=aqueduct. (B) Schematic midsagittal section of mouse cerebellum at day of birth. The Purkinje cell layer (PCL) is located underneath the EGL and secretes Shh which is received by EGL cells and drives their extensive proliferation such that granule cells become the most abundant neurons in the cerebellum and in the entire brain. Upon differentiation, EGL cells migrate through the PCL layer to form the IGL of the mature cerebellum. Their trailing axons form the molecular layer (ML). Purkinje cells project into the cerebellar white matter (WM). Drawings are not to scale

Figure 2. Spectrum of human cerebellar malformations on MRI

Top row: Axial images at the level of the midbrain-hindbrain junction (isthmus). Bottom row: Midline sagittal images. In normal, isthmus shape is relatively circular, and cerebellar vermis is full. In all of the conditions except rhombencephalosynapsis the cerebellar vermis is hypoplastic (double arrows on bottom row). In Joubert syndrome (JSRD) the isthmus takes the shape of a “molar tooth” (arrows). In Dandy-Walker malformation (DWM), the posterior fossa is full of fluid (white field) and bottom shows the cystic dilatation of the fourth ventricle (*), which is rotated anteriorly. In Pontocerebellar hypoplasia (PCH) the brainstem is also involved. Note small isthmus and vermis (arrow, top) and reduced brainstem volume (arrow, bottom). Cerebellar vermis hypoplasia (CVH) shows reduced vermis without other associated features. Rhombencephalosynapsis shows fusion of the two cerebellar hemispheres, and the vermis is replaced by this fusion. (double arrows, top).