NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord.

The first step of producing a protein involves the DNA of a gene being copied to form a molecule of RNA. This RNA molecule can often be processed to create several different “messenger” RNAs (mRNAs), each of which are used to produce a different protein by a process known as alternative splicing. A class of proteins that bind to RNA molecules controls alternative splicing. These “splicing factors” ensure that the right protein variant is produced at the right time and in the right place to carry out the appropriate activity. Many genes that play important roles in the nervous system have been reported to undergo alternative splicing to generate different protein variants. However, it is unclear whether alternative splicing is important for controlling how the nervous system develops, during which time the neurons connect to the cells that they will communicate with. Forming these connections involves part of the neuron, called the axon, growing along a precise path through the nervous system to reach its destination. If alternative splicing is important for this process, it is also important to ask: which splicing factors are relevant and which genes do these splicing factors regulate? Through genetic and molecular studies using mouse embryos, Leggere et al. found that the NOVA family of splicing factors are essential for the development of the nervous system. In particular, the NOVA splicing factors control the alternative splicing of a gene called Dcc. This gene produces proteins that play a number of roles, including helping axons to grow and guiding the axons to the correct location in the developing nervous system. A related study by Saito et al. showed that two forms of NOVA splicing factors – called NOVA1 and NOVA2 – have different roles in the nervous system, and describes the role of NOVA2 in more detail. Leggere et al. will now carry out additional studies to determine the unique role of each protein variant produced from the Dcc gene. Future research will also investigate how NOVA proteins help generate these variants at the right time and in the right place.