Delta-like Gene Research Articles

Identification and characterisation of lamprey protein kinase C delta-like gene

Protein kinase C-δ (PKC-δ), a member of the lipid-regulated serine/threonine PKC family, has been implicated in a wide range of important cellular processes, such as cell growth, differentiation, and apoptosis. Lampreys belong to the most primitive class of vertebrates, and there is little information on PKC-δ in these animals. In this study, a PKC-δ-like cDNA sequence and deduced PKC-δ-like amino acid sequence were identified in the Japanese lamprey (Lampetra japonica). The PKC-δ-like gene shared approximately 60% sequence identity with its homologs in jawed vertebrates. The anti-PKC-δ-like polyclonal antibodies were well prepared, and experiments showed that PKC-δ-like was primarily distributed in the supraneural body of the lamprey. Both mRNA and protein levels of PKC-δ-like in supraneural body cells were increased after incubation with cis-diaminedichloroplatinum (CDDP). Moreover, PKC-δ-like protein induced the apoptosis of HEK-293T cells. In addition, the activation of PKC-δ-like resulted in apoptosis. Conversely, the inhibition of PKC-δ-like activity disrupted the CDDP-mediated induction of cellular apoptosis. These results indicate that PKC-δ-like identified in lampreys might play an important role in apoptosis in jawless vertebrates.

Acheate‐scute like 1 (Ascl1) is required for normal delta‐like (Dll) gene expression and notch signaling during retinal development

Delta gene expression in Drosophila is regulated by proneural basic helix-loop-helix (bHLH) transcription factors, such as acheate-scute. In vertebrates, multiple Delta-like and proneural bHLH genes are expressed during neurogenesis, especially in the retina. We recently uncovered a relationship between Acheate-scute like 1 (Ascl1), Delta-like genes, and Notch in chick retinal progenitors. Here, we report that mammalian retinal progenitors are also the primary source of Delta-like genes, likely signaling through Notch among themselves, while differentiating neurons expressed Jagged2. Ascl1 is coexpressed in Delta-like and Notch active progenitors, and required for normal Delta-like gene expression and Notch signaling. We also reveal a role for Ascl1 in the regulation of Hes6, a proneurogenic factor that inhibits Notch signaling to promote neural rather than glial differentiation. Thus, these results suggest a molecular mechanism whereby attenuated Notch levels coupled with reduced proneurogenic activity in progenitors leads to increased gliogenesis and decreased neurogenesis in the Ascl1-deficient retina.

Dll1 and Dll4 function sequentially in the retina and pV2 domain of the spinal cord to regulate neurogenesis and create cell diversity

Signalling mediated by Notch receptors is known to have multiple functions during vertebrate neural development, regulating processes like progenitor differentiation and cell type diversification. Various Notch ligands are expressed in the developing nervous system and their activities might contribute to this multiplicity of functions. Here, we show that two Delta-like genes, Dll1 and Dll4, are sequentially expressed in differentiating neurons of the embryonic mouse retina and spinal cord's pV2 domain, with Dll1 starting to be expressed before Dll4. Analysis of Dll1 mutants reveals this gene is necessary and sufficient to maintain a pool of progenitors in the embryonic neuroepithelium. Accordingly, in the spinal cord domains where Dll1 is the only expressed Notch ligand, its inactivation leads to an increased rate of neurogenesis and premature differentiation of neural progenitors. In contrast, in the pV2 domain and retina where Dll1 is co-expressed with Dll4, progenitors are not exhausted and cell diversity is maintained. Together, our results support a model where Dll1 and Dll4 are part of a unique genetic circuitry that regulates subsequent steps of neurogenesis in the retina and pV2 domain: while Dll1 serves to prevent the untimely differentiation of neural progenitors, Dll4 might function to generate diversity within the population of differentiating neurons.

Relationship between delta‐like and proneural bHLH genes during chick retinal development

Notch signaling in the retina maintains a pool of progenitor cells throughout retinogenesis. However, two Notch-ligands from the Delta-like gene family, Dll1 and Dll4, are present in the developing retina. To understand their relationship, we characterized Dll1 and Dll4 expression with respect to proliferating progenitor cells and newborn neurons in the chick retina. Dll4 matched the pattern of neural differentiation. By contrast, Dll1 was primarily expressed in progenitor cells. We compared Dll1 and Dll4 kinetic profiles with that of the transiently up-regulated cascade of proneural basic helix-loop-helix (bHLH) genes after synchronized progenitor cell differentiation, which suggested a potential role for Ascl1 in the regulation of Delta-like genes. Gain-of-function assays demonstrate that Ascl1 does influence Delta-like gene expression and Notch signaling activity. These data suggest that multiple sources of Notch signaling from newborn neurons and progenitors themselves coordinate retinal histogenesis.

Pancreatic Development and Disease

Pancreatic Development and Disease

Notch signalling controls pancreatic cell differentiation.

The pancreas contains both exocrine and endocrine cells, but the molecular mechanisms controlling the differentiation of these cell types are largely unknown. Despite their endodermal origin, pancreatic endocrine cells share several molecular characteristics with neurons, and, like neurons in the central nervous system, differentiating endocrine cells in the pancreas appear in a scattered fashion within a field of progenitor cells. This indicates that they may be generated by lateral specification through Notch signalling. Here, to test this idea, we analysed pancreas development in mice genetically altered at several steps in the Notch signalling pathway. Mice deficient for Delta-like gene 1 (Dll1) or the intracellular mediator RBP-Jkappa showed accelerated differentiation of pancreatic endocrine cells. A similar phenotype was observed in mice over-expressing neurogenin 3 (ngn 3) or the intracellular form of Notch3 (a repressor of Notch signalling). These data provide evidence that ngn3 acts as proendocrine gene and that Notch signalling is critical for the decision between the endocrine and progenitor/exocrine fates in the developing pancreas.

Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm.

Approximately 10% of cases of Alzheimer's disease are familial and associated with autosomal dominant inheritance of mutations in genes encoding the amyloid precursor protein, presenilin 1 (PS1) and presenilin 2 (PS2). Mutations in PS1 are linked to about 25% of cases of early-onset familial Alzheimer's disease. PS1, which is endoproteolytically processed in vivo, is a multipass transmembrane protein and is a functional homologue of SEL-12, a Caenorhabditis elegans protein that facilitates signalling mediated by the Notch/LIN-12 family of receptors. To examine potential roles for PS1 in facilitating Notch-mediated signalling during mammalian embryogenesis, we generated mice with targeted disruptions of PS1 alleles (PS1-/- mice). PS1-/- embryos exhibited abnormal patterning of the axial skeleton and spinal ganglia, phenotypes traced to defects in somite segmentation and differentiation. Moreover, expression of mRNA encoding Notch1 and Dll1 (delta-like gene 1), a vertebrate Notch ligand, is markedly reduced in the presomitic mesoderm of PS1-/- embryos compared to controls. Hence, PS1 is required for the spatiotemporal expression of Notch1 and Dll1, which are essential for somite segmentation and maintenance of somite borders.

5580738 Delta-like gene expressed in neuroendocrine tumors : Laborda Jorg Rockville, MD, United States Assigned to The United States of America as represented by the Department of Health and Human Services

5580738 Delta-like gene expressed in neuroendocrine tumors : Laborda Jorg Rockville, MD, United States Assigned to The United States of America as represented by the Department of Health and Human Services

Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta.

The Drosophila Delta (Dl) gene is essential for cell-cell communication regulating the determination of various cell fates during development. Dl encodes a transmembrane protein, which contains tandem arrays of epidermal-growth-factor-like repeats in the extracellular domain and directly interacts with Notch, another transmembrane protein with similar structural features, in a ligand-receptor-like manner. Similarly, cell-cell interactions involving Delta-like and Notch-like proteins are required for cell fate determinations in C. elegans. Notch homologues were also isolated from several vertebrate species, suggesting that cell-to-cell signaling mediated by Delta- and Notch-like proteins could also underlie cell fate determination during vertebrate development. However, in vertebrates, no Delta homologues have yet been described. We have isolated a novel mouse gene, Dll1 (delta-like gene 1), which maps to the mouse t-complex and whose deduced amino acid sequence strongly suggests that Dll1 represents a mammalian gene closely related to Drosophila Delta. Dll1 is transiently expressed during gastrulation and early organogenesis, and in a tissue-restricted manner in adult animals. Between day 7 and 12.5 of development, expression was detected in the paraxial mesoderm, closely correlated with somitogenesis, and in subsets of cells in the nervous system. In adult animals, transcripts were detected in lung and heart. Dll1 expression in the paraxial mesoderm and nervous system is strikingly similar to the expression of mouse Notch1 during gastrulation and early organogenesis. The overlapping expression patterns of the Dll1 and Notch1 genes suggest that cells in these tissues can communicate by interaction of the Dll1 and Notch1 proteins. Our results support the idea that Delta- and Notch-like proteins are involved in cell-to-cell communication in mammalian embryos and suggest a role for these proteins in cellular interactions underlying somitogenesis and development of the nervous system.