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First published online 28 February 2007
doi: 10.1242/dev.000786

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The Hes gene family: repressors and oscillators that orchestrate embryogenesis

Institute for Virus Research, Kyoto University and Japan Science and Technology Agency, CREST, Kyoto 606-8507, Japan.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Structure and function of Hes factors. (A) The conserved domains of Hes factors. The basic (blue), HLH (mauve), Orange (orange) and WRPW (pink) domains and their functions are indicated. (B) Active repression: Hes factors bind to the N box or class C site by forming homodimers (left panel) or heterodimers with Hey (right panel) and actively repress transcription by interacting with co-repressors, such as Groucho homologs. (C) Passive repression: Hes factors form non-DNA-binding heterodimers with bHLH activators such as E47 and inhibit transcriptional activation. (D) Activation: bHLH activators such as Mash1 and E47 form heterodimers that bind to the E box and activate transcription.

View larger version (49K): [in this window] [in a new window]   Fig. 2. Maintenance of neural stem cells and promotion of astrocyte formation by Hes genes. (A) Regulation of cell differentiation by bHLH genes. Neuroepithelial cells initially form the neural plate. These cells gradually develop into radial glial cells, which have a cell body in the ventricular zone (VZ) and a radial fiber reaching the pial surface. Radial glial cells give rise to neurons by asymmetric cell divisions. After the production of distinct types of neurons, radial glial cells finally differentiate into astrocytes. Hes genes maintain neuroepithelial cells and radial glial cells during early development, and promote astrocyte formation during late development. Proneural genes such as Mash1, Ngn2 and Math1 promote neurogenesis. Unlike other Hes genes, Hes6 also promotes neurogenesis. The broken line indicates the border of the VZ. (B) Transfection experiments in mouse embryonic brains. Many of the cells transfected with a control vector that only drives enhanced green fluorescent protein (EGFP) expression in radial glial cells have migrated out of the VZ (at the bottom of the image) and differentiated into neurons, whereas cells transfected with a vector that directs the co-expression of Hes1 and EGFP, remain in the VZ and display radial glial cell morphology [from Ohtsuka et al. (Ohtsuka et al., 2001)]. Scale bars: 100 µm.

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View larger version (27K): [in this window] [in a new window]   Fig. 3. Differential Hes1 expression between compartments and boundaries. (A) Lateral view of the developing central nervous system (CNS) in the mouse at E10.5. The CNS is partitioned into many compartments by boundaries, such as the zona limitans intrathalamica (Zli) and the isthmus. These boundaries and the roof and floor plates function as organizing centers by expressing Shh (pink), Wnt1 (green) or Fgf8 (purple). Cells in these compartments undergo active proliferation and neurogenesis, whereas those in boundaries undergo slower proliferation and no neurogenesis. Pth, prethalamus; Th, thalamus. (B) The Hes1 expression mode is different between compartments and boundaries: (Ba) variable expression (could be oscillatory) in compartments and (Bb) persistently high expression in boundaries. In compartments, when Hes1 levels are low, Mash1 levels are high, and vice versa. These cells finally lose Hes1 expression and differentiate into neurons. By contrast, in boundaries, Hes1 is persistently expressed at high levels, and neurogenesis is inhibited. This difference in the Hes1 expression modes may confer compartment versus boundary characteristics.

View larger version (35K): [in this window] [in a new window]   Fig. 4. Regulation of pancreatic and intestinal cell differentiation by Hes1. (A) In the developing pancreas, the epithelium gives rise to both exocrine and endocrine cells; exocrine cells form acini, whereas endocrine cells emigrate from the epithelium and form islets. The bHLH gene Ptf1a regulates exocrine cell differentiation, whereas Ngn3 promotes the differentiation of all four types of pancreatic endocrine cells [ (glucagon), ß (insulin), (somatostatin) and PP (pancreatic polypeptide) cells]. Hes1 regulates the maintenance of progenitors by inhibiting the expression of Ptf1a and Ngn3. (B) In the adult small intestine, stem cells are found near the bottom of the crypt. The cells moving upwards towards the crypt top and towards the villi differentiate into goblet cells, enteroendocrine cells and enterocytes, whereas those moving downwards towards the crypt bottom differentiate into Paneth cells. Hes1 regulates stem cell maintenance and enterocyte versus non-enterocyte fate choice by repressing Math1, which promotes the development of goblet, enteroendocrine and Paneth cells.

View larger version (31K): [in this window] [in a new window]   Fig. 5. Hes genes are molecular oscillators. (A) Oscillatory expression of Hes1 is regulated by negative feedback. Promoter activation (green), as induced by Notch, for example, induces the production of Hes1 protein, which represses expression of its own gene (red). Then, both Hes1 mRNA and protein disappear rapidly because they have very short half-lives, allowing the next round of expression. In this way, Hes1 expression autonomously oscillates. (B) Hes7 oscillation in somite segmentation. (Ba) Ventral view of a mouse embryo at the five-somite stage. Somites form periodically by segmentation of the anterior region of the presomitic mesoderm (PSM, shown in blue). (Bb) Hes7 expression is periodically propagated, like a wave, from the posterior end to the anterior region of the PSM (shown by blue arrow, classified into three phases), and each wave leads to the generation of a pair of somites (buff). (Bc) This dynamic change is elicited by oscillatory expression in each PSM cell with a slight delay from the posterior to the anterior direction.

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