Recently, new alleles of Drosophila Ten m were identified and charac terized establishing that mutations in this gene do not cause segmentation defects. instead, Ten m functions in motor selleck chem Sunitinib neuron routing. Ten m is expressed in the cen tral nervous system and epidermal stripes at stages when the growth cones of intersegmental neurons navi gate to their targets. Both mutation and over expression of Ten m in epidermal cells leads to ISN misrouting. A related protein, tenascin a has a trans synaptic sig naling role with Ten m Ten a is presynaptic whereas Ten m is predominantly postsynaptic in neuromuscular synapse organization and target selection. The mouse has four teneurin transmembrane protein family members that lack signal peptides at the N terminus, but contain a short hydrophobic domain characteristic of transmembrane proteins followed by a re gion with eight EGF like repeats, and a large C terminal domain.

The vertebrate homolog of Drosophila Ten Inhibitors,Modulators,Libraries a is called Tenm1 and the homolog of Drosophila Ten m is Tenm4. All four mammalian Tenm genes are highly expressed in the brain and each gene produces many alternatively spliced transcripts, suggesting a variety of protein functions in different tissues. Novel mu tant alleles having defects in early mouse embryonic devel opment can be identified using ethylnitrosourea mutagenesis. A series of ENU induced alleles at mouse 17Rn3 contain mutations in the Tenm4 gene, which exhibit a wide array of phenotypes, ran ging from embryonic death at gastrulation to viable with skeletal defects. In two loss of function alleles, embryos fail to gastrulate.

Inhibitors,Modulators,Libraries In less severe alleles, gas trulation occurs, but body axis formation, somitogenesis, vasculogenesis, Inhibitors,Modulators,Libraries cardiogenesis, and fusion of the allantois with the chorion are disrupted leading to death at early to mid gestation stages. Consistent with these mutant phenotypes, Tenm4 is ubiquitously expressed in the epi blast and extraembryonic regions as early as E6. 5. By E7. 5, Tenm4 is highly expressed in the mesoderm of the devel oping embryo and extraembryonic Inhibitors,Modulators,Libraries tissues. Later, Tenm4 is expressed mainly in the neuroectoderm, but expression is maintained in the tail bud, somites and limbs. To begin to address the biological function of Tenm4, the loss of function allele Tenm4m1, and a hypomorphic Inhibitors,Modulators,Libraries allele Tenm4m4 were examined.

Tenm4m1/m1 mutant em bryos failed to initiate gastrulation, failed to form a primitive streak, inhibitor order us and failed to develop mesoderm. In addition, Tenm4m1/m1 mutant embryos were incapable of forming any differentiated tissue. An analysis of the hypomorphic allele, Tenm4m4, along with the null allele, determined that mutant cells did not properly express E or N cadherin, suggesting that the epithelial to mesen chymal transition did not occur. Moreover, the mutants failed to up regulate a TOPGAL reporter gene, suggesting that Wnt signaling failed to occur.