Tcf4 Controls Neuronal Migration of the Cerebral Cortex through Regulation of Bmp7

Abstract

<b>Background:</b> Transcription factor 4 (TCF4) is found to be associated with schizophrenia. TCF4 mutations also cause Pitt-Hopkins Syndrome, a neurodevelopmental disorder associated with severe mental retardation. However, the function of TCF4 during brain development remains unclear. <b>Results:</b> Here, we report that <i>Tcf4</i> is expressed in the developing cerebral cortex. <i>In utero</i> suppression of <i>Tcf4</i> arrested neuronal migration, leading to accumulation of ectopic neurons in the intermediate zone. Knockdown of <i>Tcf4</i> impaired leading process formation. Furthermore, Bone Morphogenetic Protein 7 (Bmp7) is upregulated in <i>Tcf4</i>-deficient neurons. <i>In vivo</i> gain of function and rescue experiments demonstrated that Bmp7 is the major downstream effector of <i>Tcf4</i> required for neuronal migration. <b>Conclusion:</b> Thus, we have uncovered a new <i>Tcf4</i>/<i>Bmp7</i>-dependent mechanism underlying neuronal migration, and provide insights into the pathogenesis of neurodevelopmental disorders.