Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin-proteosome system

The transcription factor Pax6 is an important developmental regulator. Spatiotemporal control of Pax6 expression during embryogenesis is crucial for regulating distinct aspects of cortical development. Here, we report that Trim11, a member of the TRIM/RBCC protein family of E3 ubiquitin ligases, interacts with Pax6 and mediates Pax6 degradation via the ubiquitin-proteasome system. Trim11 overexpression decreases endogenous Pax6 protein levels and represses Pax6 functions, including Pax6-dependent transactivation and neurogenesis. Abrogation of endogenous Trim11 expression in the developing cortex increases the level of insoluble forms of Pax6 and enhances apoptosis. We provide evidence that the B30.2 domain of Trim11 is essential for the clearance of insoluble cell proteins. Furthermore, we show that the expression of Trim11 is directly regulated by Pax6 in developing cortex in vivo. Our findings indicate that an autoregulatory feedback loop between Trim11 and Pax6 maintains a balance between the levels of Pax6 and Trim11 proteins in cortical progenitors, having an essential role for the Pax6-dependent neurogenesis.