P. Urbanek et al., COOPERATION OF PAX2 AND PAX5 IN MIDBRAIN AND CEREBELLUM DEVELOPMENT, Proceedings of the National Academy of Sciences of the United Statesof America, 94(11), 1997, pp. 5703-5708
Midbrain and cerebellum development depends on an organizing center th
at is located at the midbrain-hindbrain junction of the vertebrate emb
ryo. Expression of the two closely related transcription factors Pax2
and Pax5 overlaps spatially and temporally in this region of the devel
oping central nervous system, To study a possible interaction of these
transcription factors in midbrain and cerebellum patterning, we have
generated Pax5, Krd double mutant mice, The transgene-induced Krd muta
tion corresponds to an approximate to 7-centimorgan chromosome 19 dele
tion that eliminates the entire Pax2 locus, The heterozygous Krd mutat
ion deleting one Pax2 allele had no effect on midbrain and cerebellum
development, Moreover, only minor developmental defects were previousl
y observed at the midline of the inferior colliculus and anterior cere
bellum in mice that were homozygous for a targeted Pax5 mutation, Simi
lar morphological alterations were observed in 80% of all compound het
erozygous Pax5 (+/-) Krd (+/-) mice. However, in the remaining 20% of
compound heterozygotes, the inferior colliculi were missing, and the v
ermis of the cerebellum was severely disrupted due to the failure of t
he cerebellar primordia to fuse at the midline, Inactivation of the se
cond Pax5 allele in Pax5 (-/-) Krd (+/-) mice resulted in complete los
s of the posterior mid brain and cerebellum, as the tissue originating
from the midbrain-hindbrain boundary region was deleted in the embryo
as early as day 9.5, On the basis of these data, we propose that the
cooperation of Pax2 and Pax5 is essential for normal functioning of th
e organizing center at the midbrain-hindbrain junction.