Massive Loss of Mid- and Hindbrain Neurons during Embryonic Development of Homozygous Lurcher Mice

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Abstract
The mouse neurological mutant lurcher (Lc) results from a semidominant mutation. HeterozygousLc/+ mice are viable but ataxic becauseLc/+ Purkinje cells die by apoptosis within the first 3 weeks of life.Lc/Lcmice 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/Lcanimals did not deviate significantly from the expected 1:2:1. Homozygous lurcher mice at P0 were found to be normal under gross morphological examination. However, these mice weighed less, lacked milk in their stomach, and died within the first day of life. No resorbed embryos were found at embryonic day (E) 17.5, indicating that all homozygous lurchers survived until birth. Histological examination of P0 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 embryonic development. A particularly conspicuous consequence of theLc/Lcgenotype at birth is the complete absence of large neurons comprising the trigeminal motor nucleus. These neurons arise normally and are maintained until E15.5. However, beginning at E15.5 large numbers of pyknotic 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 muscles required for suckling, these results suggest an explanation for the neonatal death of homozygousLcanimals. These data demonstrate that the severe and dose-dependent developmental consequences oflurchergene action result from degeneration of distinct neuronal populations on maturation in the developing CNS.