The Lurcher cerebellar mutant phenotype is not expressed on a staggerer mutant background

Abstract

The hierarchy of the various processes responsible for the development of the complex, elaborated Purkinje cell can be examined by taking advantage of a series of spontaneous mutations that affect cerebellar development in the mouse. This study uses double mutants containing genes for two separate hereditary cerebellar mutations that have been shown to act intrinsically in Purkinje cells in order to investigate the time course and modes of action of these mutations. Lurcher mice show 100% degeneration of Purkinje cells, starting during the second postnatal week, while staggerer mice show reduced numbers of Purkinje cells in a distinctive mediolateral distribution from the time of birth, with the remainder grossly stunted. When these mutations are combined genetically, mice shown by progeny tests to harbor both staggerer and Lurcher genotypes exhibit staggerer-like behavior and overall cerebellar morphology; they also do not lose 100% of their Purkinje cells, as Lurcher mutants would otherwise do. Instead, they show a characteristic staggerer cerebellar pathology. We conclude that the intrinsic action of the staggerer gene in Purkinje cells occurs earlier in development than do effects of the Lurcher gene, and that the action of the staggerer gene prevents Purkinje cells from acquiring the characteristics required for the cytotoxic action of the Lurcher gene.

Massive Loss of Mid- and Hindbrain Neurons during Embryonic Development of Homozygous Lurcher Mice

“…This degeneration begins at ϳP10 with the initial massive death of Purkinje cells and is followed by the gradual disappearance of cerebellar granule cells and inferior olivary neurons. Purkinje cell death in heterozygous animals has been shown to be cell-autonomous (Wetts and Herrup, 1982a,b) and to be dependent on terminal differentiation of these large, primary cerebellar neurons (Messer et al, 1991;Norman et al, 1995). In homozygous lurcher animals, degeneration of the mid-and hindbrain neurons begins with massive death of large neurons in the trigeminal motor nucleus at ϳE15.5-E16.5.…”

Purkinje cell fate instaggerer mutants: Agenesis versus cell death

“…Staggerer (sg) is an autosomal recessive mutation that appears to cause a cell-autonomous, lineage-specific block in the development of the Purkinje cell (Herrup andMullen, 1979a,b, 1981;Messer et al, 1991;Sidman et al, 1962;Yoon, 1972). A candidate gene for staggerer, ROR␣, was recently identified as an orphan nuclear hormone receptor of the steroid, thyroid, or retinoid receptor superfamily (Hamilton et al, 1996).…”

Expression pattern of integrin ?1 subunit in purkinje cells of rat and cerebellar mutant mice

“…The appearance of spines on somata, large dendrites, and dendritic blanchlets is severely delayed in the staggerer Purkinje cells (Hirano and Dembitzer, 1975;Yoon, 1976;Messer et al, 1991). Furthermore, Yoon (1976) reported that the development of Purkinje somata was also delayed in the staggerer, and that the developmental process of Purkinje cells as a whole was either delayed or arrested.…”