THE NF2 TUMOR-SUPPRESSOR GENE-PRODUCT IS ESSENTIAL FOR EXTRAEMBRYONICDEVELOPMENT IMMEDIATELY PRIOR TO GASTRULATION

The neurofibromatosis type II (NF2) tumor suppressor encodes a putativ e cytoskeletal associated protein, the loss of which leads to the deve lopment of Schwann cell tumors associated with NF2 in humans. The NF2 protein merlin belongs to the band 4.1 family of proteins that link me mbrane proteins to the cytoskeleton and are thought to be involved in dynamic cytoskeletal reorganization. Beyond its membership in this fam ily, however, the function of merlin remains poorly understood. In ord er to analyze the function of merlin during embryogenesis and to devel op a system to study merlin function in detail, we have disrupted the mouse Nf2 gene by homologous recombination in embryonic stem cells. Mo st embryos homozygous for a mutation at the Nf2 locus fail between emb ryonic days 6.5 and 7.0, exhibiting a collapsed extraembryonic region and the absence of organized extraembryonic ectoderm. The embryo prope r continues to develop, but fails to initiate gastrulation. These obse rvations are supported by the expression patterns of markers of the ex traembryonic lineage and the lack of expression of mesodermal markers in the mutant embryos. Mosaic studies demonstrate that merlin function is not required cell autonomously in mesoderm, and support the propos ition that merlin function is essential for the development of extraem bryonic structures during early mouse development.