Postnatal Development of the Central Nervous System: Anomalies in the Formation of Cerebellum Fissures

Abstract

A natural defect in rat cerebellum postnatal development has been found in the fissura prima, consisting in various complex configurations of the cerebellar layers. We investigated the genesis of fissure malformations through immunoreactions for PCNA, GFAP, GABAA a6, and calbindin to label proliferating cells of the external granular layer (egl), radial glial fibers, mature granule cells, and Purkinje cells, respectively. Results on critical stages of rat postnatal development provided interesting evidences on how the malformation develops in fissures prima and secunda. Early (postnatal day 10) at the site of malformation, the Bergmann radial glia was often retracted and showed distortions and irregular running. The interruption of GFAP-positive radial glial fibers could fit in with the presence of clusters of PCNA-unlabeled cells in the sites of fusion of the egl; the clusters of cells are granule cells since their soma is labeled by GABAA a6. Moreover, an altered migration of granule cell precursors to the internal granular layer was evident which, in turn, affected Purkinje cell differentiation and the growth of their dendrites. In summary, the changed relationship among glial fiber morphology, granule cell migration, and Purkinje cell differentiation suggests how the Bergmann glial fibers have a basic role in the foliation process, being the driving physical force in directing migration of the granule cells at the base of fissure. Anat Rec, 293:492-501, 2010. V V C 2010 Wiley-Liss, Inc.

Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats

“…Remarkably, these malformations are almost exclusively found along the primary fissure in regions lacking pia and are characterized by granule cells present in the molecular layer that fail to migrate to the internal granule cell layer. Although other neuron and glial cell types are present in malformations [22], the overwhelming majority of cells present are granule cells expressing doublecortin [23] or alpha-6 ionotropic gammaaminobutyric acid receptors [22]. Consistent with a model of migration defect of granule cells as a primary cause of these malformations which we have termed, molecular layer heterotopia (MLH), our group and others have shown that Bergman glial cells expressing nestin [23] or glial fibrillary acidic protein [22] have disorganized radial fibers.…”

“…Although other neuron and glial cell types are present in malformations [22], the overwhelming majority of cells present are granule cells expressing doublecortin [23] or alpha-6 ionotropic gammaaminobutyric acid receptors [22]. Consistent with a model of migration defect of granule cells as a primary cause of these malformations which we have termed, molecular layer heterotopia (MLH), our group and others have shown that Bergman glial cells expressing nestin [23] or glial fibrillary acidic protein [22] have disorganized radial fibers. Moreover, migrating granule cells expressing doublecortin were found to have abnormal migratory morphologies and polarity in areas with developing heterotopia [23].…”

“…Several rat strains commonly used as disease models (e.g., Sprague-Dawley, Long-Evans, and Wistar) exhibit spontaneous neurodevelopmental malformations of the cerebellar vermis visible as early as postnatal day (P) 1 [18][19][20][21][22]. Remarkably, these malformations are almost exclusively found along the primary fissure in regions lacking pia and are characterized by granule cells present in the molecular layer that fail to migrate to the internal granule cell layer.…”

Congenital cerebellar dysplasia in White Leghorn chickens (Gallus gallus domesticus)

“…Over 95% of Purkinje cells are ectopic in the reeler mutant mouse because of complete loss of the Reelin signal, whereas one population of Purkinje cells was located in an aberrant position in math1 null-mutant mouse due to the lack of an external granular cell layer. As well as Purkinje cell heterotopy, anomalies in the folia and fissures have been suggested to be associated with defects of genetic controls in the foliation process (Cerri et al, 2010). Bergmann's glial fibres direct migration of the granular cells at the base of the fissure, and the Purkinje cells regulate the number of folia by secreting sonic hedgehog, which influences granular cell proliferation in the external granular cell layer (Corrales et al, 2006;Sudarov & Joyner, 2007).…”

“…Bergmann's glial fibres direct migration of the granular cells at the base of the fissure, and the Purkinje cells regulate the number of folia by secreting sonic hedgehog, which influences granular cell proliferation in the external granular cell layer (Corrales et al, 2006;Sudarov & Joyner, 2007). It is suggested that the genetic defects change the relationship among glial fibre morphology, granular cell migration and Purkinje cell differentiation and impede the mechanical forces of foliation, resulting in alteration of cerebellar architecture (Cerri et al, 2010). The condition in our cases was probably due to defects of radial glia fibres and related migration factors.…”