Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human

Linkage analysis and haplotype mapping in interspecific mouse crosses (Mus musculus x Mus spretus) identified the gene encoding Aurora2 (Stk6 in mouse and STK15 in human) as a candidate skin tumor susceptibility gene. The Stk6 allele inherited from the susceptible M. musculus parent was overexpressed in normal cells and preferentially amplified in tumor cells from F(1) hybrid mice. We identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors. The Ile31 variant transforms rat1 cells more potently than the more common Phe31 variant. The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the 'weak' STK15 Phe31 variant form in yeast two-hybrid screens and in human cells. This interaction results in colocalization of UBE2N with STK15 at the centrosomes during mitosis. These results are consistent with an important role for the Ile31 variant of STK15 in human cancer susceptibility.     

Muscle pioneers: large mesodermal cells that erect a scaffold for developing muscles and motoneurones in grasshopper embryos

During embryonic development, muscles differentiate in the appropriate places and motoneurone growth cones find the appropriate muscles; both events occur concurrently and with remarkable specificity. What are the cellular interactions that orchestrate this coordinated development of nerve and muscle? In the development of vertebrate skeletal muscles, motoneurone growth cones arrive in the periphery along stereotyped routes and enter the appropriately located masses of mesodermal cells usually before differentiated muscle fibres appear and before the masses cleave into separate muscles. We find that a similar sequence of events occurs in the grasshopper embryo. We are interested in how mesodermal cells become organized into the appropriate muscles and what guides motoneurone growth cones to their appropriate targets. Fortunately, in the grasshopper embryo the mesodermal cells in the periphery and motoneurones in the central nervous system (CNS) are large, accessible and in many cases individually identifiable from early in their development. We report here the discovery of a class of large mesodermal cells, which we call muscle pioneers, that arise early in development when the embryonic environment is relatively simple and distances short. By their growth and association with particular sites along the ectoderm, the muscle pioneers appear to erect a scaffold for later developing muscles and motoneurone growth cones.