In human cutaneous malignant melanoma, a predominance of activated mutations in the N-ras gene has been documented. To obtain a mouse model most closely mimicking the human disease, a transgenic mouse line was generated by targeting expression of dominant-active human N-ras (N

Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16 Ink4a gene. Melanomas also frequently exhibit constitutive activation of the Wnt/␤-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized ␤-catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16 Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized ␤-catenin bypasses the requirement for p16 Ink4a mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.[Keywords: Mitf; Wnt; senescence; development; tumor suppressor; oncogene] Supplemental material is available at http://www.genesdev.org.

The AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS.

We have analysed the importance of ®broblast growth factor 2 (FGF2) in tumor development. In a transgenic mouse model (Tyrp1-Tag) tumors form in the retinal pigment epithelium (RPE), invade surrounding tissues, and metastasize to lymph node and spleen. To address whether RPE tumor formation is dependent on FGF2, we generated FGF2-de®cient mice. Such mice appeared healthy and exhibited no impairment of growth or development. Tyrp1-Tag transgenic mice, which are lacking FGF2 (FGF27/7) developed RPE tumors that metastasize to spleen and lymph nodes. Tumor growth and survival rate are identical to Tyrp1-Tag transgenic littermates expressing FGF2. Cell lines were isolated from RPE tumors of wild-type and FGF2-de®cient mice. They grow in culture, are pigmented and form vascularized tumors, when injected subcutaneously into nude mice of either FGF27/7 or FGF2+/+ genetic background. Kinetics of tumor growth was identical and independent of presence of FGF2. Together, these results demonstrate that FGF2 is not essential for tumor formation of the RPE thus suggesting that tumor growth in general may not be dependent on FGF2.