Mouse models of Casc3 reveal developmental functions distinct from other components of the exon junction complex

Abstract

The exon junction complex (EJC) is a multiprotein complex integral to mRNA metabolism. Biochemistry and genetic studies have concluded that the EJC is composed of four core proteins, MAGOH, EIF4A3, RBM8A, and CASC3. Yet recent studies in Drosophila indicate divergent physiological functions for Barentsz, the mammalian Casc3 ortholog, raising the question as to whether CASC3 is a constitutive component of the EJC. This issue remains poorly understood, particularly in an in vivo mammalian context. We previously found that haploinsufficiency for Magoh, Eif4a3, or Rbm8a disrupts neuronal viability and neural progenitor proliferation, resulting in severe microcephaly. Here, we use two new Casc3 mouse alleles to demonstrate developmental phenotypes that sharply contrast those of other core EJC components. Homozygosity for either null or hypomorphic Casc3 alleles led to embryonic and perinatal lethality, respectively. Compound embryos lacking Casc3 expression were smaller with proportionately reduced brain size. Mutant brains contained fewer neurons and progenitors, but no apoptosis, all phenotypes explained by developmental delay. This finding, which contrasts with severe neural phenotypes evident in other EJC mutants, indicates Casc3 is largely dispensable for brain development. In the developing brain, CASC3 protein expression is substoichiometric relative to MAGOH, EIF4A3, and RBM8A. Taken together, this argues that CASC3 is not an essential EJC component in brain development and suggests it could function in a tissue-specific manner.