Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences

Abstract

Over the last 60 years, the spotlight of research has periodically returned to the cerebellum as new techniques and insights have emerged. Because of its simple homogeneous structure, limited diversity of cell types and characteristic behavioral pathologies, the cerebellum is a natural home for studies of cell specification, patterning, and neuronal migration. However, recent evidence has extended the traditional range of perceived cerebellar function to include modulation of cognitive processes and implicated cerebellar hypoplasia and Purkinje neuron hypo-cellularity with autistic spectrum disorder. In the light of this emerging frontier, we review the key stages and genetic mechanisms behind cerebellum development. In particular, we discuss the role of the midbrain hindbrain isthmic organizer in the development of the cerebellar vermis and the specification and differentiation of Purkinje cells and granule neurons. These developmental processes are then considered in relation to recent insights into selected human developmental cerebellar defects: Joubert syndrome, Dandy-Walker malformation, and pontocerebellar hypoplasia. Finally, we review current research that opens up the possibility of using the mouse as a genetic model to study the role of the cerebellum in cognitive function.

Keywords: autism spectrum disorders; behavior; cerebellum; defects; development; function; genetics; hypoplasia.

FIGURE 1

Developmental origins of the mouse cerebellum and the role of isthmic gene expression in patterning the vermis. (A) Schematic representation of a mid-gestation embryo showing the location of derivatives of rhombomere 1. The ventricular layer (green) and rhombic lip (brown) of dorsal rhombomere 1 give rise to all GABA-ergic and glutamatergic cells of the cerebellum, respectively. (B) In a dorsal (posterior) view, the adult cerebellum is characterized by a central (darker shaded) vermis running anterior (ant) to posterior (pos). A uniform layering of cell types can be found throughout the vermis and more lateral hemispheres (shown in schematic parasagittal section), with GABA-ergic and glutamatergic differentially distributed in a later-specific manner: the molecular layer is largely reserved for the interaction of Purkinje cell dendrites and granule cell axons with sparse basket and stellate inhibitory interneurons. The Purkinje cells layer separates the molecular layer from an internal granule cell layer that contains a population of inhibitory Golgi cells. Deep cerebellar nuclei (GABA-ergic and glutamatergic neurons) lie within the white matter. (C) Schematic diagram showing the location of the isthmus organizer at the midbrain/hindbrain boundary with respect to the fourth ventricle roof plate (rp) and the expression domains of Wnt1 (purple) and Fgf8 (blue). (D) Dorsal schematic view of the isthmus region showing with darker shading the approximate region where progenitors of the cerebellar vermis reside, as based on inducible fate-mapping studies (Sgaier et al., 2005). The translation of this dorsal rhombomere 1 territory into adult vermis is shown inset. (E) Altered morphology of the isthmic region and reduced cerebellar size in a hypomorph with an altered function of the isthmic organizer due to diminished FGF signaling. Loss of vermis progenitors is concomitant with the expansion of the roof plate (adapted from Basson et al., 2008). The consequences for vermal morphogenesis in the adult are shown inset.

FIGURE 2

Cellular development of cerebellum and components of the re-entrant cortico-cerebellar loop. (A) Schematic cross sectional view through the anlage of the cerebellum showing the relationship between rhombic lip (rl), ventricular zone (vz), and roof plate (rp) of the fourth ventricle. Adult morphological layering (Figure1) is the product of two major migration pathways. The vz gives rise to GABA-ergic radially dispersed Purkinje cells (oc). The rl generates glutamatergic deep cerebellar nucleus (dcn) neurons and granule cell precursors of the external germinal layer (egl), which migrate tangentially from the rl in sub-pial streams. (B) Postnatally, the egl proliferates under the influence of Purkinje cell-derived Shh. Postmitotic glutamatergic granule cells migrate radially from the EGL to internal granule layer (igl). In mutants where Purkinje cells are deleted, or in which Shh is depleted, or where egl formation is suppressed (as in the Atoh1 knockout mouse), cerebellum growth is reduced. Disruptions in signals from the overlying mesenchyme, directly or through affecting signaling from the roof plate, may modulate the responsiveness of the egl to mitogens, thus abrogating its expansion. (C) From data derived in the primate (Strick et al., 2009) a general model for a mammalian circuit would propose that cortico-cerebellar closed loops modulate cortical activity for a number of different motor and non-motor cortical areas. Without presupposing details of cortical areas in the mouse, cortical activity would be anticipated to feed into the cerebellar circuit via the pontine nucleus, a derivative of the rhombic lip of the hindbrain. Cerebellar output via dentate nucleus neurons would then feed back to the cortical areas via the thalamus.