Transverse boundaries divide the cerebellar cortex into four transverse zones, and within each zone the cortex is further subdivided into a symmetrical array of parasagittal stripes. Several molecules believed to mediate long-term depression at the parallel fiber-Purkinje cell synapse are known to be expressed in stripes. We have therefore explored the distributions of phospholipase Cbeta3 and phospholipase Cbeta4, key components in the transduction of type 1 metabotropic glutamate receptor-mediated responses. The data reveal that both phospholipase Cbeta isotypes are expressed strongly in the mouse cerebellum in subsets of Purkinje cells. The two distributions are distinct and largely nonoverlapping. The pattern of phospholipase Cbeta3 expression is unique, revealing stripes in three of the four transverse zones and a uniform distribution in the fourth. In contrast, phospholipase Cbeta4 appears to be confined largely to the Purkinje cells that are phospholipase Cbeta3-negative. PLCbeta3 is restricted to the zebrin II-immunopositive Purkinje cell subset. Not all zebrin II-immunoreactive Purkinje cells express PLCbeta3: in lobules IX and X it is restricted to that zebrin II-immunopositive subset that also expresses the small heat shock protein HSP25. PLCbeta4 expression is restricted to, and coextensive with, the zebrin II-immunonegative Purkinje cell subset. These nonoverlapping expression patterns suggest that long-term depression may be manifested differently between cerebellar modules.
Niemann Pick disease type C1 (NPC1) is an inherited, autosomal recessive, lipid-storage disorder with major neurological involvement. Purkinje cell death is a prominent feature of the neuropathology of NPC. We have investigated Purkinje cell death in two murine models of NPC1, BALB/c npc(nih) and C57BLKS/J spm. In both cases, extensive Purkinje cell death was found in the cerebellum. The pattern of Purkinje cell death is complex. First, zebrin II-negative Purkinje cells disappear, to leave survivors aligned in stripes that closely resemble the pattern revealed by using zebrin II immunocytochemistry. Subsequently, as the disease progresses, additional Purkinje cells die. At the terminal stages of the disease, the surviving Purkinje cells are concentrated in lobules IX and X of the posterior lobe vermis. Purkinje cell degeneration is accompanied by the ectopic expression of tyrosine hydroxylase and the small heat shock protein HSP25, both associated preferentially with the surviving cells. The pattern of cell death thus reflects the fundamental compartmentation of the cerebellum into zones and stripes.
Purkinje cells in the cerebellum express the antigen zebrin II (aldolase C) in many vertebrates. In mammals, zebrin is expressed in a parasagittal fashion, with alternating immunopositive and immunonegative stripes. Whether a similar pattern is expressed in birds is unknown. Here we present the first investigation into zebrin II expression in a bird: the adult pigeon (Columba livia). Western blotting of pigeon cerebellar homogenates reveals a single polypeptide with an apparent molecular weight of 36 kDa that is indistinguishable from zebrin II in the mouse. Zebrin II expression in the pigeon cerebellum is prominent in Purkinje cells, including their dendrites, somata, axons, and axon terminals. Parasagittal stripes were apparent with bands of Purkinje cells that strongly expressed zebrin II (+ve) alternating with bands that expressed zebrin II weakly or not at all (-ve). The stripes were most prominent in folium IXcd, where there were seven +ve/-ve stripes, bilaterally. In folia VI-IXab, several thin stripes were observed spanning the mediolateral extent of the folia, including three pairs of +ve/-ve stripes that extended across the lateral surface of the cerebellum. In folium VI the zebrin II expression in Purkinje cells was stronger overall, resulting in less apparent stripes. In folia II-V, four distinct +ve/-ve stripes were apparent. Finally, in folia I (lingula) and X (nodulus) all Purkinje cells strongly expressed zebrin II. These data are compared with studies of zebrin II expression in other species, as well as physiological and neuroanatomical studies that address the parasagittal organization of the pigeon cerebellum.
The mammalian cerebellum is located in the posterior cranial fossa and is critical for motor coordination and non-motor functions including cognitive and emotional processes. The anatomical structure of cerebellum is distinct with a three-layered cortex. During development, neurogenesis and fate decisions of cerebellar primordium cells are orchestrated through tightly controlled molecular events involving multiple genetic pathways. In this review, we will highlight the anatomical structure of human and mouse cerebellum, the cellular composition of developing cerebellum, and the underlying gene expression programs involved in cell fate commitments in the cerebellum. A critical evaluation of the cell death literature suggests that apoptosis occurs in ~5% of cerebellar cells, most shortly after mitosis. Apoptosis and cellular autophagy likely play significant roles in cerebellar development, we provide a comprehensive discussion of their role in cerebellar development and organization. We also address the possible function of unfolded protein response in regulation of cerebellar neurogenesis. We discuss recent advancements in understanding the epigenetic signature of cerebellar compartments and possible connections between DNA methylation, microRNAs and cerebellar neurodegeneration. Finally, we discuss genetic diseases associated with cerebellar dysfunction and their role in the aging cerebellum.
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