Abstract
Transcription factor Pax6 is a key regulator of progenitor cells in the mammalian telencephalon and eye, and it is also expressed during the development of the cerebellum. Studies using Pax6 knock out (KO) mice have revealed its critical role for the prenatal generation and migration of cerebellar granule cell progenitors as well as for the establishment of progenitor domains in the hindbrain. However, the perinatal mortality of these mice hindered the study of the role of Pax6 during postnatal cerebellar development, which is the period when most granule neurons are born in mammals.Here we used the Cre/loxP system to conditionally inactivate Pax6 in the cerebellum of developing and adult mice, which allowed us to investigate viable mutants. To this goal, we generated a novel transgenic mouse Cre line, in which the Cre recombinase is placed behind a Pax6 regulatory sequence. Crossing this Cre line with reporter lines (ZAP and ROSA26-lacZ) demonstrated the strongest activity in the cerebellum, especially in the anterior lobes, while weaker expression was detected in telencephalon, eye and pancreas. We then crossed the Pax6Cre line with the Pax6flox/flox transgenic mice carrying loxP sequences allowing inactivation of Pax6 function upon Cre expression. The double-mutant mice were viable and thus allowed us to investigate the effects of Pax6 loss-of-function (LOF) for postnatal cerebellar development. The mutants exhibited significantly diminished cerebellum with abnormal foliation, especially in the anterior lobes, coincident with the strongest Cre activity. The mice had ectopic clusters of Purkinje cells in the white matter surrounded by granule cells and GABAergic neurons. Thus, the Pax6Cre::Pax6flox/flox transgenic mice appear a useful tool to study the consequences of postnatal LOF of Pax6 in the cerebellum.
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