The floating head (flh) gene in zebrafish encodes a homeodomain protein, which is essential for notochord formation along the entire body axis. flh orthologs, termed Not genes, have been isolated from chick and Xenopus, but no mammalian ortholog has yet been identified. Truncate (tc) is an autosomal recessive mutation in mouse that specifically disrupts the development of the caudal notochord. Here, we demonstrate that truncate arose by a mutation in the mouse Not gene. The truncate allele (Not , and Not tc/tc embryos is very similar but slightly more severe in Not eGFP/eGFP than in Not tc/tc embryos. This confirms allelism of truncate and Not, and indicates that tc is not a complete null allele. Not expression is abolished in Foxa2 and T mutant embryos, suggesting that Not acts downstream of both genes during notochord development. This is in contrast to zebrafish embryos, in which flh interacts with ntl (zebrafish T) in a regulatory loop and is essential for development of the entire notochord, and suggests that different genetic control circuits act in different vertebrate species during notochord formation.

The high risk human papillomavirus (HPV) type 16 E7 protein a ects cell growth control and promotes transformation by interfering with functions of cellular proteins. A key target of E7 is the tumor suppressor protein p105RB. Although this interaction is required for E7-dependent transformation, other cellular molecules must also be involved, because some E7 mutants that have reduced transforming abilities still bind to p105RB. In order to identify additional proteins that interact with E7 and that may be responsible to mediate its transforming function, we have used the C-terminal half of E7 in a yeast two-hybrid screen. We identi®ed the fork head domain transcription factor M phase phosphoprotein 2 (MPP2) as an interaction partner of E7. Speci®c interaction of the two proteins both in vitro and in vivo in mammalian cells was detected. The interaction of MPP2 with E7 is functionally relevant since MPP2 enhances the E7/Ha-Ras co-transformation of rat embryo ®broblasts. In addition HPV16 E7, but neither non-transforming mutants of HPV16 E7 nor low risk HPV6 E7, was able to stimulate MPP2-speci®c transcriptional activity. Thus, MPP2 is a potentially important target for E7-mediated transformation.

The neural cell adhesion molecule (NCAM) and its post-translational modification polysialic acid (polySia) are broadly implicated in neural development. Mice lacking the polysialyltransferases ST8SiaII and ST8SiaIV are devoid of polySia, and show severe malformation of major brain axon tracts. Here, we demonstrate how allelic variation of three interacting gene products (NCAM, ST8SiaII and ST8SiaIV) translates into various degrees of anterior commissure, corpus callosum and internal capsule hypoplasia. Loss of ST8SiaII alone caused mild, but distinct defects and the severity of the pathological phenotype found in mice lacking both polysialyltransferases could be stepwise attenuated by reducing NCAM expression. Analysis of mice with overall nine selected combinations of mutant NCAM and polysialyltransferase alleles revealed that the extent of the fibre tract deficiencies was not linked to the total amount of polySia or NCAM, but correlated strictly with the level of NCAM erroneously devoid of polySia during brain development. The defects implemented by the gain of polySia-free NCAM were reminiscent to abnormalities found in patients with schizophrenia. Since variations in NCAM1 and ST8SIA2 have been implicated in schizophrenia, these findings provide a mechanism how genetic interference with the complex coordination of NCAM polysialylation may lead to a neurodevelopmental predisposition to schizophrenia.

Mitogen-activated protein kinase phosphatase 1 (MKP-1) is negatively regulating mitogen-activated protein kinases and is therefore involved in early signaling processes. The expression of the mkp-1 gene is induced by growth factors and stress. The promoters of the human and murine mkp-1 genes contain several conserved DNA binding elements, including two cAMP response elements and an E box. We observed that the upstream stimulatory factor (USF), but not c-Myc, activated mkp-1. USF synergized with protein kinase A, thus providing evidence for a role of the E box, during signal-regulated stimulation of mkp-1.z 2000 Federation of European Biochemical Societies.