Dissection of the cellular and molecular events that position cerebellar Purkinje cells: a study of the math1 null-mutant mouse.

ABSTRACT

Granule cell precursors in the external germinal layer (EGL) of the cerebellum have been proposed to be a major player in the migration and positioning of Purkinje cells through the expression of the Netrin-like receptor Unc5h3 and the extracellular matrix molecule Reelin. To explore the role of the EGL on these processes, we made use of the math1 null-mutant mouse in which the EGL does not form. In the absence of the EGL, we find three populations of ectopic Purkinje cells. First, we find 1% of all Purkinje cells in a supracerebellar position at the dorsal midline. Second, we find 7% of all Purkinje cells in the inferior colliculus, similar to what is seen in the Unc5h3 mutant. Our finding that Unc5h3 expression is not disrupted in these cells supports the proposed role of EGL granule cell precursors in establishing the anterior cerebellar boundary through the expression of Unc5h3. Third, we find 20% of all Purkinje cells positioned deep to the cerebellar cortex as seen in the reeler mutant. However, unlike the reeler mutant, where 5% of the Purkinje cells migrate successfully, we find that in the math1 null that 72% of the Purkinje cells migrate successfully. This finding demonstrates that Purkinje cell migration is not solely dependent on Reelin signaling from the EGL and is likely caused by Reelin signals emanating from the nuclear transitory zone or the ventricular zone, or both.