ABNORMAL EMBRYONIC CEREBELLAR DEVELOPMENT AND PATTERNING OF POSTNATALFOLIATION IN 2 MOUSE ENGRAILED-2 MUTANTS

The cerebellum is an ideal system to study pattern formation in the ce ntral nervous system because of its simple cytoarchitecture and regula r organization of folds and neural circuitry. Engrailed-2 (En-2) is ex pressed in a spatially restricted broad band around the mesencephalic- metencephalic junction, a region from which the cerebellum is derived. Mice homozygous for a targeted deletion of the En-2 homeobox, En-2(hd ), previously have been shown to have an altered adult cerebellar foli ation pattern. To address whether the En-2(hd) allele was hypomorphic, we generated a putative null mutation that makes an N-terminal deleti on (ntd). Mice homozygous for this new mutation, En-2(ntd), display an identical cerebellar patterning defect, suggesting that both alleles represent null alleles. We also examined the developmental profile of En-2 homozygous mutant cerebellar foliation. This revealed a complex p henotype of general developmental delay and abnormal formation of spec ific fissures with the most severe morphological disruptions being lim ited to the posterior region of the cerebellum. The expression of two transgenes, which express lacZ in lobe-specific patterns in the cerebe llum, also was found to be altered in En-2 homozygotes, suggesting pos sible lobe transformations. Finally, during embryogenesis there was a clear delay in fusion of the cerebellar rudiments at the midline by 15 .5 d.p.c. This and the expression pattern of En-2 suggests that althou gh cerebellar foliation is largely a postnatal process, the patterning of the cerebellum may begin during embryogenesis and that En-2 plays a critical role in this early process.