A recent study showed that Wen-Hsuan Chang have described about Ryk and its chaperone contribution for the brain’s cortex development and which is the gray matter is responsible for consciousness. This study got published in the Proceedings of the National Academy of the Sciences (PNAS).

The receptor-like tyrosine kinase (Ryk), a Wnt receptor, is important for cell fate determination during corticogenesis. During neuronal differentiation, the Ryk intracellular domain (ICD) is cleaved. Cleavage of Ryk and nuclear translocation of Ryk-ICD are required for neuronal differentiation.

However, the mechanism of translocation and how it regulates neuronal differentiation remain unclear. Here, we identified Smek1 and Smek2 as Ryk-ICD partners that regulate its nuclear localization and function together with Ryk-ICD in the nucleus through chromatin recruitment and gene transcription regulation.

 Smek1/2 double knockout mice displayed pronounced defects in the production of cortical neurons, especially interneurons, while the neural stem cell population increased. In addition, both Smek and Ryk-ICD bound to the Dlx1/2 intergenic regulator element and were involved in its transcriptional regulation.

These findings demonstrate a mechanism of the Ryk signaling pathway in which Smek1/2 and Ryk-ICD work together to mediate neural cell fate during corticogenesis. A newly featured protein in this study, during cortical development, a part of Ryk called the intracellular domain (ICD).

ICD must be chaperoned into the nucleus of the stem cells that become neurons. Chang's team discovered the identity of Ryk's chaperone: a protein named Smek. Smek not only chaperones Ryk into the nucleus, which contains the stem cell's genes. Smek also works with Ryk to regulate the activity of key genes that transform stem cells into brain cells.

Wange Lu said that these findings not only help us to understand the mechanisms of stem cells become neurons, but it is also useful for us to develop therapies for treating neurological diseases and brain cancer.