International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Howell GR, Wilson L, Munroe RJ, Schimenti JC

The Jackson Laboratory, Bar Harbor, United States

A region-specific ENU mutagenesis screen has identified 38 embryonic lethal phenotypes (termed L5Jcs1 to L5Jcs38) based on “loss of class” at wean.  Due to the nature of the screen each of the lethal mutations could be localised to a 40 Mb region of mouse chromosome 5, delineated by the Rump white (Rw) inversion.

The recessive phenotype, apt1 (anterior-posterior transformation 1, formally known as L5Jcs1) was originally identified as an embryonic lethal (based on the “loss of class” at wean). Studies now show that mice homozygous for the mutation develop to around e18.5 days, but are either born dead, or survive until around one day post-partum. A more detailed analysis of the skeleton of apt1 mice revealed a posterior to anterior transformation of the thoracic and lumbar vertebrae, similar to abnormalities seen in a number of Hox gene knockouts. Specifically, the eighth rib (thoracic segment 8 – T8) is attached to the sixth sternabra, and the first lumbar vertebra (L1) shows the development of a fourteenth rib. Judging by the rib length it also appears that the ninth to the thirteenth thoracic segments (T9-13) are potentially transformed into more anterior structures. Recombination mapping (carried out in collaboration with Dr Maja Bucan’s lab, Univ Penn, Philadelphia) localised apt1 to a 6.3 Mb region on proximal mouse chromosome 5, between D5Mit353 and D5Mit107. In combination with recombinational mapping, mapping by complementation was also carried out to narrow the region of interest using a series of overlapping deletions generated around the Qdpr gene. Skeletal preparations of deletion/apt1 mice showed the same homeotic-like transformation as apt1/apt1 mice, and this analysis narrowed the critical region to 3 Mb containing only 14 genes.

RNA was recovered from mutant and wild type mice and all genes in the region were screened for mutations by PCR and sequencing. A splice site mutation, causing exon skipping, has been identified in a novel transmembrane protein and confirmation by BAC rescue is underway. This novel gene provides the basis for furthering our understanding of the mechanisms involved in the development of anterior-posterior structures in mice.

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