DCX in PC12 cells: CREB-mediated transcription and neurite outgrowth.

Mutations in doublecortin (DCX) result in X-linked lissencephaly in males. To explore the role of DCX in differentiation and signal transduction we overexpressed DCX in PC12 cells. Our results indicate that DCX stabilizes microtubules and inhibits neurite outgrowth in nerve growth factor-induced differentiation. However, neurite length is increased when differentiation is induced by epidermal growth factor and forskolin or by dibutyryl-cAMP. Furthermore, CREB-mediated transcription is downregulated, supporting the notion that cytoskeletal regulatory proteins can affect the transcriptional state of a cell. Using different constructs and mutations we reach the conclusion that microtubule stabilization is a key factor, but not the only one, in controlling neurite extension. Overexpression of a mutation found in a lissencephaly patient (S47R), completely blocks neurite outgrowth. We propose that these functions are important during normal and abnormal brain development.