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 non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitterspecific 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 Ponto-cerebellar 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.

Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex

“…In contrast, genetic and molecular means to identify, characterize, or manipulate basket, stellate and Golgi cells, candelabrum neurons, Lugaro cells or unipolar brush cells have been largely elusive. It is not surprising, then, that these cells are typically not considered even in recent integrative views of cerebellar function (e.g., Apps and Garwicz 2005;Porrill et al 2004;Boyden et al 2004); at best, the more prominent Lugaro cells and unipolar brush cells are mentioned, and rather in passing (e.g., Ito 2008;Millen and Gleeson 2008).…”

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

“…3 In the developing cerebellum and brainstem, primary cilia regulate major signal transduction pathways, and have been implicated in both neuronal cell proliferation and axonal migration. 4 In particular, primary cilia are required for Sonic Hedgehog (SHH) signaling and for SHHdependent cerebellar development, [5][6][7] including in humans. 8 Here we report a novel homozygous missense ARL13B variant in a consanguineous Joubert patient from Tunisia with retinal involvement and obesity.…”

Optimized Immunohistochemical Analysis of Cerebellar Purkinje Cells Using a Specific Biomarker, Calbindin D28k

“…PC axons pass through the granular layer (GL) and white matter (WM) and terminate at deep cerebellar nuclei (Sotelo, 2004;Douyard et al, 2007;Cheron et al, 2008). Many insults, such as ischemia, toxins, infections, and genetic changes, directly or indirectly lead to destructive disturbances of PCs, which are associated with spinocerebellar ataxias (Koeppen, 2005;Millen and Gleeson, 2008). Thus, a pathophysiological understanding of the cellular changes of PCs can provide clues to therapeutic strategy developments for treating cerebellar disorders.…”