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

Brain Struct Funct (2014) 219:3547 DOI 10.1007/s00429-012-0482-6

ORIGINAL ARTICLE

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

Roy V. Sillitoe Nicholas A. George-Jones

Kathleen J. Millen Richard Hawkes

Received: 20 July 2012 / Accepted: 1 November 2012 / Published online: 18 November 2012 Springer-Verlag Berlin Heidelberg 2012

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 specication 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 specic lobules in the vermis. To distinguish between an ectopic and absent

vermis, the expression patterns of two Purkinje cell-specic 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 pheno-type, 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.

Keywords Whole-mount immunohistochemistry

HSP25 Zebrin II Cerebellar development Lmx1a

Introduction

The spontaneous neurological mutant dreher is one of many mouse models used to understand cellular behaviors during nervous system development. Positional cloning revealed that an autosomal recessive mutation in Lmx1a, encoding a LIM-homeodomain transcription factor, is responsible for the dreher phenotype (Millonig et al. 2000). The mutation results in abnormal formation of the roof plate and adjacent cerebellar rhombic lip, two structures that express Lmx1a during embryonic...