Hes genes differ from other bHLH factors in that they have a proline reside in the middle of the basic DNA binding region. This proline has been proposed to give Hes proteins unique DNA binding capacity. Hes proteins also heterodimerize with bHLH repressors such as Hey1 and Hey2 , a process which also blocks transcription. Hes factors also heterodimerize with bHLH activators such as E47, also known as Tcfe2a, and Mash1, also known as Ascl1 , both of which are the mammalian homologs to proneural genes in Drosophila.
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Hes genes differ from other bHLH factors in that they have a proline reside in the middle of the basic DNA binding region.
This proline has been proposed to give Hes proteins unique DNA binding capacity. Hes proteins also heterodimerize with bHLH repressors such as Hey1 and Hey2 , a process which also blocks transcription.
Hes factors also heterodimerize with bHLH activators such as E47, also known as Tcfe2a, and Mash1, also known as Ascl1 , both of which are the mammalian homologs to proneural genes in Drosophila. Specifically, HES1 influences the timing of differentiation by repressing bHLH activators, and determines binary cell fate. HES1 has been shown to play a large role in both the nervous , and digestive systems.
HES1 has been shown to influence these two systems partially through the Notch signaling pathway. Neural development[ edit ] HES1 is expressed in both neuroepithelial cells and radial glial cells , both neural stem cells. Hes1 expression, along with that of Hes5, covers the majority of the developing embryo at embryonic day Indeed, if the expression of Hes1, Hes3, and Hes5 genes is inhibited, the expression of proneural genes increases, and while neurogenesis is accelerated, neural stem cells become prematurely depleted.
Contrariwise, if these HES genes are overexpressed, neurogenesis is inhibited. Additionally, HES1 can guide neural stem cells down one of two paths of differentiation. HES1 can maintain neural stem cells expressing Pax6 , but leads cells that are Pax6-negative to an astrocyte differentiation fate. Demethylation of HES1 target sites in the promoter region of astrocyte-specific genes hastens astrocyte differentiation.
HES1-high embryonic stem cells that received a differentiation signal often adopted a mesodermal fate, while HES1-low cells that received a differentiation signal differentiated into neuronal cells. These results were confirmed using quantitative PCR which showed that HES1-high cells showed high levels of Brachyury and Fgf5 expression both of which are expressed highly in mesodermal cell types with comparatively low levels genes expressed in neural cells such as Nestin.
By contrast, HES1-low cells showed high levels of expression of genes involved in neural induction and low levels of expression of genes involved in mesodermal differentiation. This suggests that alternating HES1 levels may prompt differences in characteristics between anatomical elements of the central nervous system.
After Notch signals have been processed within the cell, however, the plasma membrane releases the intracellular domain of Notch, which moves to the nucleus where it associates with RBPJ.
The binding causes a conformational change which leads co-repressors to disassociate and allows co-activators to bind. The new activating complex then prompts HES1 expression. Notch signaling activates HES1 expression. Hyperactivated Notch causes a reduction in the number of secretory cell types i.
Deletion of the Notch pathway by removing the Notch expression controller, Rbpsuh, causes the production of nearly only goblet cells. In pancreatic progenitor cells , HES1 expression inhibits the expression of Ptf1a , which controls exocrine cell differentiation, and Ngn3 , which drives differentiation of endocrine cell types that will form the islets of Langerhans.
When Hes1 is deleted in mouse and zebrafish, surplus goblet cells and enteroendocrine cells are made while few enterocytes are made. When Hes1 expression is low, hepatocytes form normally, but bile ducts are completely absent.
Therefore, Hes-Notch interactions also play a role in digestive organ development.
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