MASSIVE LOSS OF MIDBRAIN AND HINDBRAIN NEURONS DURING EMBRYONIC-DEVELOPMENT OF HOMOZYGOUS LURCHER MICE

The mouse neurological mutant lurcher (Lc) results from a semidominant mutation. Heterozygous Lc/+ mice are viable but ataxic because Lc/+ P urkinje cells die by apoptosis within the first 3 weeks of life. Lc/Lc mice die shortly after birth. To aid in understanding the function of the lurcher gene product, we have examined the embryonic development of homozygous lurcher animals. The ratio of +/+:Lc/+:Lc/Lc animals did not deviate significantly from the expected 1:2:1. Homozygous lurcher mice at PO were found to be normal under gross morphological examinat ion. However, these mice weighed less, lacked milk in their stomach, a nd died within the first day of life. No resorbed embryos were found a t embryonic day (E) 17.5, indicating that all homozygous lurchers surv ived until birth. Histological examination of PO animals revealed that in homozygous lurcher mice the patterning of the brain is normal but that there has been a massive loss of hindbrain neurons during embryon ic development. A particularly conspicuous consequence of the Lc/Lc ge notype at birth is the complete absence of large neurons comprising th e trigeminal motor nucleus. These neurons arise normally and are maint ained until E15.5. However, beginning at E15.5 large numbers of pyknot ic cells are evident in the trigeminal motor nucleus, suggesting that these cells die coincident with their terminal differentiation in the developing hindbrain. Because the trigeminal motor nucleus controls mu scles required for suckling, these results suggest an explanation for the neonatal death of homozygous Lc animals. These data demonstrate th at the severe and dose-dependent developmental consequences of lurcher gene action result from degeneration of distinct neuronal populations on maturation in the developing CNS.