Because the lateral rectus muscle is encompassed by the myodome, the VIth nerve must pass through this structure in order to innervate its target. The myodome appears to be unique to fishes, but with a possible functional equivalent in the cavernous and intercavernous sinuses of man. The bones making up the walls of the myodome have a novel paraxial mesoderm embryonic origin in the chick, unlike most other components of the cranium which originate from migratory neural crest cells. The expression of CPA6 in this tissue suggests a role for CPA6 in the unique specification of cartilaginous tissue from paraxial mesoderm which may be linked to a phylogenetic remodeling of this tissue to enable the VIth nerve to pass and successfully find its target muscle. However, morpholino-mediated knockdown of CPA6 did not result in any visible defects in the trajectory of the VIth nerve nor in any behavioral eye movement defects specific to either the medial or lateral rectus muscle. The conserved expression of CPA6 in cartilaginous precursors posterior to the eye. This conundrum between the specific localization of CPA6 adjacent to the lateral rectus muscle and yet lack of a behavioral phenotype upon knockdown might be explained in several ways. First, new mechanisms for VIth nerve development may have evolved in mammalian systems that involve the phylogenetic remodeling of cartilaginous/skeletal elements through the actions of CPA6. Alternatively, CPA6 may have taken on a role in mammalian axon pathfinding that simply is not present in teleost fish. Another possibility is that developmental and molecular characteristics of the abducens motor ARRY-142886 neurons and the VIth nerve itself may have evolved. This is suggested by anatomical differences between teleost and mammalian abducens nuclei. Abducens motoneurons arise from two nuclei found in hindbrain rhombomeres 5 and r6 in the zebrafish, while mammalian abducens motor neurons arise from only one nucleus found in r5. Axons of r5 abducens motoneurons, the sole population in mammals, may require CPA6 for guidance while axons of r6 motoneurons, when present in teleost fish, may be able to reach their target in a CPA6independent manner and provide guidance for other CPA6dependent axons. However, no anatomical or physiological differences between r5 and r6 abducens motor neurons have yet to be discovered. Another possibility for the lack of a CPA6 knockdown phenotype may be the involvement of other genes, acting in a compensatory manner in the zebrafish, or defective in reported cases of Duane syndrome but yet undetected. Recent reports have suggested that CPA6 may not be the sole causative Duane syndrome gene on chromosome 8, but the duplication of another more centromeric gene, CHD7, may be involved. The reported chromosomal translocation disrupting the 59 end of the CPA6 gene in a Duane syndrome patient might also affect promoter/enhancer elements of neighboring genes. The CPA6 gene is arranged in a head-to-head fashion with the DEPDC2 gene, which encodes a Rac-GEF with broad.