Disease relevance of notch1a

• Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis [1].

High impact information on notch1a

• Here we analyse a set of zebrafish mutants and arrive at a different interpretation: the essential function of Notch signalling in somite segmentation is to keep the oscillations of neighbouring presomitic mesoderm cells synchronized [2].
• This phenotype has prompted many investigations, but the role of Notch signalling in somitogenesis remains mysterious [2].
• Important progress has been made in dissecting the roles of bone morphogenetic protein, Wnt and Notch signalling systems and their associated downstream transcription factors in the control of neural crest cell differentiation [3].
• Here, we show evidence that a Hes6-related hairy/Enhancer of split-related gene, her13.2, links FGF signaling to the Notch-regulated oscillation machinery in zebrafish [4].
• In irradiated adults, Notch activity induced runx1 gene expression and increased multilineage hematopoietic precursor cells approximately threefold in the marrow [5].

Biological context of notch1a

• We find that mutations in zebrafish integrinalpha5 disrupt anterior somite formation, giving a phenotype complementary to the posterior defects seen in the notch pathway mutants after eight/deltaD and deadly seven/notch1a [6].
• Consistent with this, combining a reduction of her7 and her1 function with a Delta/Notch mutant genotype does not worsen the phenotype further [7].
• The oscillator, or clock, is thought to create a prepattern of stripes of gene expression that regulates the activity of the Notch pathway that subsequently directs somite border formation [8].
• Recent findings indicate that, paradoxically, endocytosis of a membrane-spanning ligand may up-regulate receptor activity: the zebrafish E3 ligase Mind bomb promotes the endocytosis of Delta and is required for efficient activation of Notch [9].
• Notch activation inhibits neuronal differentiation during development of the nervous system; however, the dynamic role of Notch signaling in individual cell lineages remains poorly understood [10].

Anatomical context of notch1a

• To investigate this segregation of the blastoderm into cells with either endodermal or mesodermal fates, we analyzed the role of Notch signaling in this process [11].
• Altogether, these results suggest that Notch signaling plays a role in the formation of the endoderm, possibly in its segregation from the mesoderm [11].
• Somitogenesis has been linked both to a molecular clock that controls the oscillation of gene expression in the presomitic mesoderm (PSM) and to Notch pathway signaling [8].
• Our results indicate that olig3 has an essential proneural activity in the dorsal spinal cord and cooperates with the Delta/Notch regulatory loop to establish the boundary between the neural crest and the lateral neural plate [12].
• Delta/Notch signaling is required for neural crest formation. ngn1 is expressed in primary neurons; inhibiting Ngn1 activity prevents Rohon-Beard cell formation but not formation of other primary neurons [13].

Associations of notch1a with chemical compounds

• Receptor tyrosine phosphatase psi is required for Delta/Notch signalling and cyclic gene expression in the presomitic mesoderm [14].
• In the Xenopus pronephros, Evi1 expression is upregulated by retinoid signaling and repressed by overexpression of xWT1 and by Notch signaling [15].

Physical interactions of notch1a

• The 3.4 kb her4 promoter contains five predicted Su(H) binding sites of which two proximal sites were confirmed to be required for Notch-mediated transcriptional activation [10].

Regulatory relationships of notch1a

• Conversely, ectopic, unregulated Notch activity blocked no tail expression and promoted her4 expression [16].
• Surprisingly, and in sharp contrast to other members of the E(spl) gene family, transcription of her3 is repressed rather than activated by Notch signalling [17].
• Delta/Notch signaling promotes formation of zebrafish neural crest by repressing Neurogenin 1 function [13].
• The low Notch activity in epidermal ionocyte progenitors is permissive for activating winged helix/forkhead box transcription factors of foxi3a and foxi3b [18].
• Histone deacetylase 1 is required to repress Notch target gene expression during zebrafish neurogenesis and to maintain the production of motoneurones in response to hedgehog signalling [19].
• Whereas DeltaD endocytosis following interaction in trans activates Notch in a neighboring cell, endocytosis of DeltaD and Notch following an interaction in cis is likely to inhibit Notch signaling by making both unavailable at the cell surface [20].

Other interactions of notch1a

• Dose dependent, posteriorly-restricted segmentation defects were seen in the dlc knock down, and in combination with the deltaD or notch1a mutants [21].
• The interaction of HER genes with the Delta/Notch signaling system was investigated by introducing a loss of her7 function into mutant backgrounds [7].
• We have examined interrelationships of her3 with members of the Notch signalling pathway by the Gal4-UAS technique and mRNA injections [17].
• Activation of Notch signaling from an early stage leads to a reduction of endodermal cells, as assessed by sox17 and foxA2 expression [11].
• The results of overexpression/gain-of-function and of morpholino-mediated loss-of-function experiments show that Her6 and Her4 are Notch signalling effectors that feedback on the clock and take part in the maintenance of cyclic gene expression coordination among adjacent cells in the presomitic mesoderm [22].

Analytical, diagnostic and therapeutic context of notch1a

• Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells [23].

References