Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition

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http://www.nature.com/natureneuroscience/

Web End = Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition

http://www.nature.com/natureneuroscience

Ryoichiro Kageyama, Toshiyuki Ohtsuka, Hiromi Shimojo & Itaru Imayoshi

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In the developing mammalian nervous system, neural progenitor cells rst express the Notch effector Hes1 at variable levels and then proneural genes and Notch ligands in salt-and-pepper patterns. Recent real-time imaging analysis indicates that Hes1 expression in these cells oscillates with a period of about 23 h. Furthermore, the proneural gene Neurogenin-2 (Ngn2) and the Notch ligand gene Deltalike-1 (Dll1) are expressed cyclically in neural progenitor cells under the control of Hes1 oscillation but are expressed continuously in postmitotic neurons, which lose Hes1 expression. Hes1-driven Ngn2 and Dll1 oscillations seem to be advantageous for maintenance of a group of cells in an undifferentiated state by mutual activation of Notch signaling. This dynamic mode of gene expression would require a revision of the traditional view of how Notch-mediated lateral inhibition operates in the developing mammalian nervous system.

The Notch signaling pathway regulates cell differentiation by means of intercellular communication between adjacent cells13. In the developing mammalian nervous system, the products of the proneural genes Mash1 and Ngn2 induce expression of Notch ligands such as Deltalike1 (Dll1), which activate Notch signaling in neighboring cells4 (Fig. 1). Upon activation, the transmembrane protein Notch is processed and releases the Notch intracellular domain (NICD), which moves from the transmembrane region to the nucleus, where it forms a complex with the DNA-binding protein RBPj. The NICD-RBPj complex then induces expression of the basic helix-loop-helix factors Hes1 and Hes5, which repress expression of proneural genes (and Notch ligand genes), thereby inhibiting neuronal differentiation and maintaining neural progenitor cells13 (Fig. 1). This intercellular regulation is called lateral inhibition because it inhibits the neighboring cells from becoming the same cell type. In the absence of this pathway, allneuralprogenitors prematurely differentiate into early-born cell types without giving rise to a sufcient number and a full spectrum of cells. Thus, the Notch signaling pathway leads to production of a diversity of cell types from apparently equivalent cells and is essential in formation of complex brain structures.

The classic view of Notch signaling In the developing mammalian nervous system, neural progenitors initially undergo proliferation only, and...