The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development

Abstract

Dendritic spines are small, actin-rich protrusions on the surface of dendrites that receive the majority of excitatory synaptic inputs in the brain. The formation and remodeling of spines, processes that underlie synaptic development and plasticity, are regulated in part by Eph receptor tyrosine kinases. However, the mechanism by which Ephs regulate actin cytoskeletal remodeling necessary for spine development is not fully understood. Here, we report that the Rac1 guanine nucleotide exchange factor Tiam1 interacts with the EphB2 receptor in a kinase-dependent manner. Activation of EphBs by their ephrinB ligands induces the tyrosine phosphorylation and recruitment of Tiam1 to EphB complexes containing NMDA-type glutamate receptors. Either knockdown of Tiam1 protein by RNAi or inhibition of Tiam1 function with a dominant-negative Tiam1 mutant blocks dendritic spine formation induced by ephrinB1 stimulation. Taken together, these findings suggest that EphBs regulate spine development in part by recruiting, phosphorylating, and activating Tiam1. Tiam1 can then promote Rac1-dependent actin cytoskeletal remodeling required for dendritic spine morphogenesis.synapses ͉ Rho GTPase ͉ actin cytoskeleton ͉ NMDA receptor

Tyrosine Phosphorylation of the Rho Guanine Nucleotide Exchange Factor Trio Regulates Netrin-1/DCC-Mediated Cortical Axon Outgrowth

“…For instance, tyrosine phosphorylation of ephexin-1, a GEF for RhoA, Cdc42, and Rac1, induces a shift in its exchange activity toward RhoA, thus promoting ephrin-A-mediated growth cone collapse (49). Vav2 and Tiam1 are also two GEFs that are regulated by phosphorylation during ephrin-Eph-mediated axon guidance (50,51). Furthermore, the activity of the Rac-GAP ␣2-chimerin is stimulated by Src family kinase-dependent phosphorylation downstream of ephrin-A1/EphA4, resulting in growth cone collapse (52).…”

Eph/ephrin molecules—a hub for signaling and endocytosis

“…TIAM1, a GEF with specificity for Rac1, is critical for Eph/ephrin-mediated neurite outgrowth and dendritic spine development Tolias et al 2007). TIAM1 also plays an important role in Eph/ephrin endocytosis ( Fig.…”

Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury

“…Constitutively activated Rac1 increases the rate of dendritic spine turnover, spine density and stability, and spine volume (Nakayama and Luo 2000). In contrast, dominant negative Rac1 expression or administration of a Rac1-specific inhibitor NSC23766 disrupts dendritic spine formation and development (Tan et al 2011;Tan and Waxman 2012;Tashiro et al 2000;Tolias et al 2007). Importantly, SCI increases Rac1 mRNA expression, with levels that can remain elevated for up to 3 mo or more (Dubreuil et al 2003;Erschbamer et al 2005).…”