Alternative titles; symbols
HGNC Approved Gene Symbol: DLL1
Cytogenetic location: 6q27 Genomic coordinates (GRCh38) : 6:170,282,206-170,291,078 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q27 | Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures | 618709 | Autosomal dominant | 3 |
The DLL1 gene encodes a Notch (see 190198) ligand. Notch signaling is essential for appropriate cell differentiation and cell fate decisions, and plays a role in developmental, homeostatic, and disease processes. DLL1 is a human homolog of the Drosophila Notch ligand Delta, and plays an important role in the developing nervous system and somites (summary by Gray et al., 1999; Fischer-Zirnsak et al., 2019).
Using PCR with degenerate primers based on the Drosophila Delta sequence to screen a placenta cDNA library, followed by probing fetal brain cDNA libraries, Gray et al. (1999) isolated a cDNA encoding DLL1, which they called Delta1. Sequence analysis predicted that the 723-amino acid DLL1 transmembrane protein, which is 88% identical to the mouse Dll1 protein, has a DSL domain followed by 8 tandem EGF-like repeats and a short cytoplasmic C-terminal region. Northern blot analysis revealed strongest expression of 4.0- and 4.6-kb transcripts in heart and pancreas, with lower expression in brain and muscle and almost no expression in placenta, lung, liver, and kidney. In situ hybridization analysis indicated upregulated expression of DLL1 in squamous cell carcinoma and in situ and invasive adenocarcinoma.
By screening a heart cDNA library with a mouse Dll1 probe, followed by RT-PCR on bone marrow endothelial cells, Han et al. (2000) obtained a cDNA encoding DLL1. SDS-PAGE and immunoblot analyses indicated expression of a 79-kD protein in endothelial cells.
Functional analysis by Han et al. (2000) suggested that a soluble fusion protein containing the DSL domain of DLL1 and its adjacent 50 N-terminal amino acids increased the viability of hemopoietic cells but inhibited cell death. Clonogenic analysis showed that the fusion protein inhibited the differentiation of myeloid progenitors but promoted their expansion.
Jaleco et al. (2001) used a cell coculture assay to show that DLL1 blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor. In contrast, JAG1 did not disturb either B-cell or T-cell/NK-cell development. The authors concluded that the interplay of NOTCH receptors with distinct ligands results in different cell fate decision processes in human lymphopoiesis.
Ikeuchi and Sisodia (2003) showed that the Notch ligands Delta1 and Jagged2 (602570) are subject to presenilin (PS1; 104311)-dependent, intramembranous gamma-secretase processing, resulting in the production of soluble intracellular derivatives. The authors also showed that the Delta1 intracellular domain (DICD) that is generated by the gamma-cleavage is transported into the nucleus and likely plays a role in transcriptional events. The authors proposed that the Jagged2 intracellular domain (JICD) would play a similar role.
Conboy et al. (2003) analyzed injured muscle and observed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient upregulation of the Notch ligand Delta and thus diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Conboy et al. (2003) concluded that Notch signaling is a key determinant of muscle regenerative potential that declines with age.
Schmitt et al. (2004) reported that embryonic stem cells (ESCs) could be induced to differentiate into functional T cells by the engagement of ESC Notch receptors by DLL1 expressed on a stromal cell line. T-lineage progenitors derived from ESC-stromal cell cocultures reconstituted the T-cell compartment of immunodeficient Rag2 (179616) -/- mice, which were then capable of mounting an effective antigen-specific cytotoxic T-lymphocyte immune response to lymphocytic choriomeningitis virus.
Galceran et al. (2004) found that mouse Lef1 (153245) bound multiple sites in the Dll1 promoter in vitro and in vivo, and mutation of the Lef1 sites impaired expression of a reporter transgene in the presomitic mesoderm of embryonic mice.
Activation of Delta genes, such as Delta1, by proneural factors is an evolutionarily conserved step in neurogenesis that results in activation of Notch signaling and maintenance of an undifferentiated state in a subset of neural progenitors. Castro et al. (2006) showed that activation of mouse Delta1 involved cooperative binding of Mash1 (ASCL1; 100790) and Brn1 (POU3F3; 602480)/Brn2 (POU3F2; 600494) to an evolutionarily conserved motif in the Delta1 gene.
To investigate how Delta both transactivates Notch neighboring cells and cis-inhibits Notch in its own cell, Sprinzak et al. (2010) developed a quantitative time-lapse microscopy platform for analyzing Notch-Delta signaling dynamics in individual mammalian cells. By controlling both cis- and trans-Delta concentrations, and monitoring the dynamics of a Notch reporter, Sprinzak et al. (2010) measured the combined cis-trans input-output relationship in the Notch-Delta system. The data revealed a striking difference between the responses of Notch to trans- and cis-Delta: whereas the response to trans-Delta is graded, the response to cis-Delta is sharp and occurs at a fixed threshold, independent of trans-Delta. Sprinzak et al. (2010) developed a simple mathematical model that shows how these behaviors emerge from the mutual inactivation of Notch and Delta proteins in the same cell. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta/low Notch) and receiving (high Notch/low Delta) signaling states. At the multicellular level, this switch can amplify small differences between neighboring cells even without transcription-mediated feedback. Sprinzak et al. (2010) concluded that this Notch-Delta signaling switch facilitates the formation of sharp boundaries and lateral-inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviors.
Rios et al. (2011) characterized the signaling events taking place during morphogenesis of chick skeletal muscle, and showed that muscle progenitors present in somites require the transient activation of NOTCH signaling to undergo terminal differentiation. The NOTCH ligand Delta1 is expressed in a mosaic pattern in neural crest cells that migrate past the somites. Gain and loss of Delta1 function in neural crest modifies NOTCH signaling in somites, which results in delayed or premature myogenesis. Rios et al. (2011) concluded that the neural crest regulates early muscle formation by a unique mechanism that relies on the migration of Delta1-expressing neural crest cells to trigger the transient activation of NOTCH signaling in selected muscle progenitors. This dynamic signaling guarantees a balanced and progressive differentiation of the muscle progenitor pool.
Chakrabarti et al. (2018) showed that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSCs-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3 (165330), Wnt10A (606268), and Wnt16 (606267), thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs.
Using FISH, Gray et al. (1999) mapped the DLL1 gene to chromosome 6q27.
In 14 patients from 11 unrelated families with neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (NEDBAS; 618709), Fischer-Zirnsak et al. (2019) identified heterozygous mutations in the DLL1 gene (see, e.g., 606582.0001-606582.0005). None of the mutations, which were found by exome sequencing, were present in the gnomAD database. All but 1 of the mutations were nonsense, frameshift, or splicing; the 1 missense variant (C179F) occurred at a conserved residue. The mutations occurred throughout the gene and there were no apparent genotype/phenotype correlations. The variants occurred de novo in 6 patients and were inherited from an affected parent in 4 patients from 2 families; the transmission pattern was unknown in the other 4 individuals. Functional studies of the variants and studies of patient cells were not performed, except to confirm the splicing defect, but all variants were predicted to result in haploinsufficiency. An additional patient (patient 15) had a de novo deletion encompassing both the DLL1 and FAM120B (612266) genes. Fischer-Zirnsak et al. (2019) noted that DLL1 plays an important role in NOTCH signaling, with a particular role in neuronal differentiation during development of the central nervous system.
Because Dll1 deficiency in mice is embryonically lethal (Hrabe de Angelis et al., 1997), Hozumi et al. (2004) used a Cre-loxP system to delete the gene after birth. Dll1 deficiency resulted in the complete disappearance of splenic marginal zone B cells without affecting T-cell development. These results suggested that Dll1 is dispensable as a Notch1 ligand at the branch point of T-cell/B-cell development, but remains essential for the generation of marginal zone B cells. Hozumi et al. (2004) concluded that Notch signaling is essential for lymphocyte development in vivo, but there is a redundancy of Notch-Notch ligand signaling that enables thymic T-cell development.
Krebs et al. (2003) showed that mouse embryos mutant for the Notch ligand Dll1 or doubly mutant for Notch1 and Notch2 (600275) exhibited multiple defects in left-right asymmetry. Dll1 -/- embryos did not express Nodal (601265) in the region around the node. Analysis of the enhancer regulating node-specific Nodal expression revealed binding sites for Rbpj (RBPSUH; 147183). Mutation of these sites destroyed the ability of the enhancer to direct node-specific gene expression in transgenic mice. Krebs et al. (2003) concluded that Dll1-mediated Notch signaling is essential for generation of left-right asymmetry, and that perinodal expression of Nodal is an essential component of left-right asymmetry determination in mice.
In a 3-year-old girl (individual 1) with neurodevelopmental disorder with nonspecific brain abnormalities and without seizures (NEDBAS; 618709), Fischer-Zirnsak et al. (2019) identified a de novo heterozygous c.1492G-T transversion (c.1492G-T, NM_005618.3) in exon 9 of the DLL1 gene, resulting in a glu498-to-ter (E498X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In 3 sibs (family 2) with neurodevelopmental disorder with nonspecific brain abnormalities and without seizures (NEDBAS; 618709), Fischer-Zirnsak et al. (2019) identified a heterozygous c.231C-A transversion (c.231C-A, NM_005618.3) in exon 2 of the DLL1 gene, resulting in a cys77-to-ter (C77X) substitution. The mutation, which was found by exome sequencing, was inherited from the affected mother. The mutation was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In an 8-year-old boy (individual 6) with neurodevelopmental disorder with nonspecific brain abnormalities and seizures (NEDBAS; 618709), Fischer-Zirnsak et al. (2019) identified a heterozygous c.1525C-T transition (c.1525C-T, NM_005618.3) in exon 9 of the DLL1 gene, resulting in an arg509-to-ter (R509X) substitution. The mutation, which was found by exome sequencing, was inherited from the affected father. The mutation was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In 2 unrelated boys (individuals 7 and 9) with neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (NEDBAS; 618709), Fischer-Zirnsak et al. (2019) identified a heterozygous 2-bp deletion (c.2013_2014del, NM_005618.3) in exon 9 of the DLL1 gene, predicted to result in a frameshift and premature termination (Glu673GlyfsTer15). The mutation, which was found by exome sequencing, occurred de novo in patient 9; parental DNA was not available for patient 7. The mutation was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In a 35-year-old woman (individual 12) with neurodevelopmental disorder with nonspecific brain abnormalities and seizures (NEDBAS; 618709), Fischer-Zirnsak et al. (2019) identified a de novo heterozygous G-to-A transition in intron 1 of the DLL1 gene (c.54+1G-A, NM_005618.3), predicted to result in a splice site alteration. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Analysis of patient cells showed that the mutation resulted in a splicing defect and an in-frame insertion of 4 amino acids (Gln18_Val19insIleGlyGlyGln) that was predicted to alter the cleavage site and result in a mature protein with 4 additional amino acids at the N terminus. Functional studies of the variant were not performed, but the variant was predicted to cause at least functional haploinsufficiency.
Castro, D. S., Skowronska-Krawczyk, D., Armant, O., Donaldson, I. J., Parras, C., Hunt, C., Critchley, J. A., Nguyen, L., Gossler, A., Gottgens, B., Matter, J.-M., Guillemot, F. Proneural bHLH and Brn proteins coregulate a neurogenic program through cooperative binding to a conserved DNA motif. Dev. Cell 11: 831-844, 2006. [PubMed: 17141158] [Full Text: https://doi.org/10.1016/j.devcel.2006.10.006]
Chakrabarti, R., Celia-Terrassa, T., Kumar, S., Hang, X., Wei, Y., Choudhury, A., Hwang, J., Peng, J., Nixon, B., Grady, J. J., DeCoste, C., Gao, J., van Es, J. H., Li, M. O., Aifantis, I., Clevers, H., Kang, Y. Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche. Science 360: eaan4153, 2018. Note: Electronic Article. [PubMed: 29773667] [Full Text: https://doi.org/10.1126/science.aan4153]
Conboy, I. M., Conboy, M. J., Smythe, G. M., Rando, T. A. Notch-mediated restoration of regenerative potential to aged muscle. Science 302: 1575-1577, 2003. [PubMed: 14645852] [Full Text: https://doi.org/10.1126/science.1087573]
Fischer-Zirnsak, B., Segebrecht, L., Schubach, M., Charles, P., Alderman, E., Brown, K., Cadieux-Dion, M., Cartwright, T., Chen, Y., Costin, C., Fehr, S., Fitzgerald, K. M., and 26 others. Haploinsufficiency of the Notch ligand DLL1 causes variable neurodevelopmental disorders. Am. J. Hum. Genet. 105: 631-639, 2019. [PubMed: 31353024] [Full Text: https://doi.org/10.1016/j.ajhg.2019.07.002]
Galceran, J., Sustmann, C., Hsu, S.-C., Folberth, S., Grosschedl, R. LEF1-mediated regulation of Delta-like1 links Wnt and Notch signaling in somitogenesis. Genes Dev. 18: 2718-2723, 2004. [PubMed: 15545629] [Full Text: https://doi.org/10.1101/gad.1249504]
Gray, G. E., Mann, R. S., Mitsiadis, E., Henrique, D., Carcangiu, M.-L., Banks, A., Leiman, J., Ward, D., Ish-Horowitz, D., Artavanis-Tsakonas, S. Human ligands of the Notch receptor. Am. J. Path. 154: 785-794, 1999. [PubMed: 10079256] [Full Text: https://doi.org/10.1016/S0002-9440(10)65325-4]
Han, W., Ye, Q., Moore, M. A. S. A soluble form of human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells. Blood 95: 1616-1625, 2000. [PubMed: 10688816]
Hozumi, K., Negishi, N., Suzuki, D., Abe, N., Sotomaru, Y., Tamaoki, N., Mailhos, C., Ish-Horowicz, D., Habu, S., Owen, M. J. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nature Immun. 5: 638-644, 2004. [PubMed: 15146182] [Full Text: https://doi.org/10.1038/ni1075]
Hrabe de Angelis, M., McIntyre, J., II, Gossler, A. Maintenance of somite borders in mice requires the Delta homologue Dll1. Nature 386: 717-721, 1997. [PubMed: 9109488] [Full Text: https://doi.org/10.1038/386717a0]
Ikeuchi, T., Sisodia, S. S. The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent 'gamma-secretase' cleavage. J. Biol. Chem. 278: 7751-7754, 2003. [PubMed: 12551931] [Full Text: https://doi.org/10.1074/jbc.C200711200]
Jaleco, A. C., Neves, H., Hooijberg, E., Gameiro, P., Clode, N., Haury, M., Henrique, D., Parreira, L. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194: 991-1001, 2001. [PubMed: 11581320] [Full Text: https://doi.org/10.1084/jem.194.7.991]
Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., Gridley, T. Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev. 17: 1207-1212, 2003. [PubMed: 12730124] [Full Text: https://doi.org/10.1101/gad.1084703]
Rios, A. C., Serralbo, O., Salgado, D., Marcelle, C. Neural crest regulates myogenesis through the transient activation of NOTCH. Nature 473: 532-535, 2011. [PubMed: 21572437] [Full Text: https://doi.org/10.1038/nature09970]
Schmitt, T. M., de Pooter, R. F., Gronski, M. A., Cho, S. K., Ohashi, P. S., Zuniga-Pflucker, J. C. Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nature Immun. 5: 410-417, 2004. [PubMed: 15034575] [Full Text: https://doi.org/10.1038/ni1055]
Sprinzak, D., Lakhanpal, A., LeBon, L., Santat, L. A., Fontes, M. E., Anderson, G. A., Garcia-Ojalvo, J., Elowitz, M. B. Cis-interactions between Notch and Delta generate mutually exclusive signalling states. Nature 465: 86-91, 2010. [PubMed: 20418862] [Full Text: https://doi.org/10.1038/nature08959]