Regulation and Function of Apoer2 and Vidlr in the Central Nervous and Reproductive Systems

The LDL receptor gene family is an evolutionarily ancient family of membrane spanning proteins composed of a diverse collection of receptors that share common domains and mediate a variety of organismal functions. Members of this family, Apoer2 and Vldlr, are highly similar receptors and are both involved in the Reelin signaling pathway. This pathway controls neuronal migration and organization of the brain during development as well as synaptic function in adulthood. Although both receptors partially compensate for one another during Reelin signaling, the generation of knockin mutant animals has allowed us to begin to uncover the unique and independent functions of these receptors that have not yet been explored. For example, a single amino acid mutation in Vldlr determines binding of the Pafah1b complex to the cytoplasmic tail of the receptor. Mice expressing this L838R mutation were created using ES cell homologous recombination techniques and will be useful in exploring the effects of the mutation in brain development and synaptic function in vivo. Vldlr independent functions that are unique to Apoer2 have been explored in more depth. These include binding of scaffolding proteins PSD95 and JIPs to an alternatively spliced exon within the cytoplasmic tail of Apoer2, which is not found in any other LDLR family member. This exon has been shown to mediate increased LTP induction after Reelin stimulation. Apoer2 knockin animals, expressing splice variants lacking another alternatively spliced exon encoding the O-linked sugar domain, show receptor stabilization through the inhibition of Apoer2 proteolytic processing. This causes increased Apoer2 levels in both the brain and testis. While lack of exon 16 has no known consequences in the testis, it does cause disrupted synaptic transmission and defective LTP induction after reelin stimulation in the brain. Apoer2 was recently found to be involved in selenium uptake into the testis and brain. Through the use of various Apoer2 intracellular domain mutant mice, a differentiation was made between the Apoer2 functional domains involved in cell signaling and the function of the receptor in selenium endocytosis. Further use of the aforementioned knockin mouse lines will help uncover previously unexplored functions of Vldlr and Apoer2 and advance our understanding of their potential involvement in neurological diseases such as Alzheimer's disease.