Despite some basic similarities, individual cell types in the nervous system are extraordinarily complex in their molecular composition. In other words, individual, mature neuron types are not defined by the expression of unique genes, but rather by a neuron type-specific combination of genes with each member of a battery more broadly expressed.
p21-Activated Kinases 1 and 3 Coordinating Neuronal Complexity
p21-activated kinases (PAKs) are a family of serine/threonine proteins. It can be activated by multiple signaling molecules, particularly the Rho family small GTPases, the central regulators of the cytoskeletal structure. PAKs (PAK1 to -3) are studied for their in vitro functions, of which the regulation of cell motility, migration, morphology, and cytoskeleton reorganization is best known. Studies on neurons also indicate that PAKs are very important for neurite outgrowth, neuronal migration, spine morphology, and synaptic and behavioral plasticity.
PAK1 and PAK3 are coexpressed in the developing brain. To explore the function of PAK1 and PAK3, scientists generated and analyzed PAK1/PAK3 double-knockout mice (DK) mice. Results show that the DK mice were born healthy, with normal brain mass. However, the DK brain failed to grow normally. The body weights of the DK mice were not affected at birth or maturity. Histological fluorosis staining of brain sections also indicated that the DK brain was smaller at maturity than the WT brain but normal at birth. The DK neurons have smaller soma, markedly simplified dendritic arbors/axons, and reduced synapse density, which was also be observed in further study. It demonstrates that neuronal complexity controlled by PAKs is a key determinant for postnatal brain enlargement and synaptic properties.
Understanding what produces neuronal diversification has been a long-standing challenge for neuroscientists. Alternative RNA splicing and RNA editing contribute to the neuronal complexity in molecular level.
Alternative RNA Splicing
Alternative RNA splicing is a versatile mechanism for generating a large repertoire of functionally unique proteins and occurs particularly frequently in the nervous system within neuronal genes, such as those for neurotransmitter receptors, ion channels, synaptic surface receptors, axon-guidance receptors, and transcription factors. The importance of alternative splicing in the nervous system became evident following the association of aberrantly spliced mRNAs with several neurological diseases. A striking example of complex alternative splicing is the Drosophila axon-guidance receptor (DSCAM), which is a homolog of the human Down’s syndrome cell-adhesion molecule. The alternatively spliced exons each encode immunoglobulin half domains that combine to create a receptor with as many as 38,016 different protein variants—double the predicted number of genes in the Drosophila genome.
RNA Editing
Similar to RNA splicing, RNA editing alters the sequence of RNA from the encoded DNA by changing as few as one or two nucleotides. Alterations include converting one base to another, removing one nucleotide and substituting another, deleting encoded residues, and inserting non-template nucleotides.
The mammalian editing enzymes, adenosine deaminases acting on RNA (ADARs), are widely expressed in several tissues; however, all known edited RNAs occur only in the CNS. The importance of such enzymes was revealed through gene knockouts in different systems. Although ADAR knockouts in flies and worms lead to behavioral abnormalities, knockouts in mammals have shown them to be essential for life. Furthermore, mRNA glutamate receptor editing is crucial for neuronal survival, and reduction of RNA editing might be a direct cause of selective motor neuron death in amyotrophic lateral sclerosis patients.
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