The nucleolar δ isoform of adapter protein SH2B1 enhances morphological complexity and function of cultured neurons

The adapter protein SH2B1 is recruited to neurotrophin receptors, including TrkB (also known as NTRK2), the receptor for brain-derived neurotrophic factor (BDNF). Herein, we demonstrate that the four alternatively spliced isoforms of SH2B1 (SH2B1 alpha-SH2B1 delta) are important determinants of neuronal architecture and neurotrophin-induced gene expression. Primary hippocampal neurons from Sh2b1(-/-) [knockout (KO)] mice exhibit decreased neurite complexity and length, and BDNF-induced expression of the synapse-related immediate early genes Egr1 and Arc. Reintroduction of each SH2B1 isoform into KO neurons increases neurite complexity; the brain-specific delta isoform also increases total neurite length. Human obesity-associated variants, when expressed in SH2B1 delta, alter neurite complexity, suggesting that a decrease or increase in neurite branching may have deleterious effects that contribute to the severe childhood obesity and neurobehavioral abnormalities associated with these variants. Surprisingly, in contrast to SH2B1 alpha, SH2B1 beta and SH2B1 gamma, which localize primarily in the cytoplasm and plasma membrane, SH2B1 delta resides primarily in nucleoli. Some SH2B1 delta is also present in the plasma membrane and nucleus. Nucleolar localization, driven by two highly basic regions unique to SH2B1 delta, is required for SH2B1 delta to maximally increase neurite complexity and BDNF-induced expression of Egr1, Arc and FosL1.