Purkinje cell compartmentalization in the cerebellum of the spontaneous mutant mouse dreher

Abstract

The cerebellar morphological phenotype of the spontaneous neurological mutant mouse dreher (Lmx1adr-J) results from cell fate changes in dorsal midline patterning involving the roof plate and rhombic lip. Positional cloning revealed that the gene Lmx1a, which encodes a LIM homeodomain protein, is mutated in dreher, and is expressed in the developing roof plate and rhombic lip. Loss of Lmx1a causes reduction of the roof plate, an important embryonic signaling center, and abnormal cell fate specification within the embryonic cerebellar rhombic lip. In adult animals, these defects result in variable, medial fusion of the cerebellar vermis and posterior cerebellar vermis hypoplasia. It is unknown whether deleting Lmx1a results in displacement or loss of specific lobules in the vermis. To distinguish between an ectopic and an absent vermis, the expression patterns of two Purkinje cell specific compartmentation antigens, zebrin II/aldolase C and the small heat shock protein HSP25, were analyzed in dreher cerebella. The data reveal that despite the reduction in volume and abnormal foliation of the cerebellum, the transverse zones and parasagittal stripe arrays characteristic of the normal vermis are present in dreher, but may be highly distorted. In dreher mutants with a severe phenotype, zebrin II stripes are fragmented and distributed non-symmetrically about the cerebellar midline. We conclude that although Purkinje cell agenesis or selective Purkinje cell death may contribute to the dreher phenotype, our data suggest that aberrant anlage patterning and granule cell development lead to Purkinje cell ectopia, which ultimately causes abnormal cerebellar architecture in dreher.

Disruption of actin‐binding domain‐containing Dystonin protein causes dystonia musculorum in mice

“…The cerebellar nucleus of Dst Gt homozygotes showed reduction in c‐jun expression (Fig. ); this region receives motor inputs from Purkinje cells and several regions in the brainstem (including the pontine nucleus) and spinal cord (Sillitoe et al ., ), and sensory input from the cuneate nucleus in the medulla oblongata, which showed a reduction in Arc and c‐jun expression (Supporting Information Fig. S5).…”

Origins, Development, and Compartmentation of the Granule Cells of the Cerebellum

“…Studies by Chizhikov et al ( 2006 ) led to an appreciation of this extra-cerebellar signaling center. The loss of LMX1A expression from roof plate cells results in both a major loss of GCs (Sekiguchi et al, 1992 ) and the ablation of the vermis (Millonig et al, 2000 ; Sillitoe et al, 2014 ). Lmx1a is also expressed in a subset of rhombic lip progenitors that produce GCs predominantly restricted to the cerebellar posterior vermis.…”

Regulation of early cerebellar development

“…The specification of EGL cells depends on intrinsic rhombic lip and extrinsic cell mechanisms. For instance, the expression of Lmx1a in the roof plate and rostral rhombic lip is critical for the generation of the choroid plexus and the specification of a subset of EGL cells destined to populate the cerebellar vermis [97][98][99]102,162,163]. In particular, the ablation of Lmx1a leads to the precocious exit of EGL cells from the rhombic lip, which change their location from the posterior to the anterior vermis [67,68,70,98,99].…”