We are interested in the molecular pathways required for differentiation of Purkinje cells, large output neurons of the cerebellar cortex. One approach we have taken is positional cloning of mouse mutations that disrupt Purkinje cell differentiation. One mutant in particular, staggerer , has been of special interest. Purkinje cells in staggerer homozygotes appear stunted and continue to express an immature repertoire of molecular markers, as if frozen in developmental time. The staggerer mutation creates a null allele of an orphan nuclear receptor, ROR a .
Nuclear receptors are a superfamily of ligand-modulated transcription factors.
Among downstream genes that fail to be expressed in staggerer cerebellum are reported targets of thyroid hormone. Thyroid hormones are known to promote neuronal maturation and are transduced through other members of the nuclear receptor family. This has suggested a level of crosstalk between nuclear receptor pathways in the development of cerebellar Purkinje cells. These experiments should provide hypotheses for the genetic architecture of neuronal differentiation, including gene ensembles for specific maturation steps. Targeted mutations of several postsynaptic signaling components of the parallel fiber-Purkinje cell synapse do not show this severe loss of synaptic competence.