Unraveling the role of SH2B1 isoforms on neuronal morphogenesis

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are key neuronal regulators. The adapter protein SH2B1 is recruited to neurotrophin receptors, and has been shown to enhance neurotrophin signaling. Interestingly, SH2B1 has four alternatively spliced isoforms, although their differential effects on neuronal outgrowth and function were unknown. A new study by Christin Carter-Su and colleagues (Cote et al., 2022) examines SH2B1 isoforms in detail. Using an Sh2b1 knockout (KO) mouse strain, the authors show that KO primary hippocampal neurons exhibit decreased neurite length and complexity and BDNF-induced gene expression. Reintroduction of each isoform into KO neurons suggests that SH2B1δ enhances neurite complexity and length to a greater extent than the other isoforms. Moreover, some human obesity-associated SH2B1 variants impair the ability of SH2B1δ to increase neurite branching. Interestingly, whereas the α, β and γ isoforms localise in the cytoplasm and plasma membrane, SH2B1δ contains two highly basic regions in its unique C-terminal tail that cause SH2B1δ to localise primarily in nucleoli. Mutational analysis experiments reveal that nucleolar localisation is in fact required for SH2B1δ function, including maximisation of neurite complexity and BDNF-dependent gene expression. Overall, this work provides insight on how the different SH2B1 isoforms regulate neuronal structure and gene expression, highlighting the contribution of nucleolar location to these functions.