<i>Dll3</i> and <i>Notch1</i> genetic interactions model axial segmental and craniofacial malformations of human birth defects

Loomes, Kathleen M.; Stevens, Stacey A.; O'Brien, Megan L.; Gonzalez, Dorian M.; Ryan, Matthew; Segalov, Michelle; Dormans, Nicholas J.; Mimoto, Mizuho S.; Gibson, Joshua D.; Sewell, William F.; Schaffer, Alyssa A.; Nah, Hyun-Duck; Rappaport, Eric; Pratt, Stephen C.; Dunwoodie, Sally L.; Kusumi, Kenro

doi:10.1002/dvdy.21296

Cited by 38 publications

(21 citation statements)

References 45 publications

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“…Together these results demonstrate that loss of Notch signaling in the cranial NC does not affect initial NCC contributions to the head or morphogenesis of craniofacial structures prior to E14.5. However, loss of Notch signaling with deletion of RBP-J in NCC-derived skeletal elements does result in defective frontal cranial suture closure and reduced bone formation in craniofacial skeletal structures apparent at E18.5, consistent with known roles for Notch signaling in cartilage lineage development and osteogenesis (Loomes et al, 2007; Mead and Yutzey, 2009). …”

Section: Resultssupporting

confidence: 63%

Notch pathway regulation of neural crest cell development in vivo

Mead

Yutzey

2012

Developmental Dynamics

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The function of Notch signaling in murine neural crest-derived cell lineages in vivo was examined. Conditional gain (Wnt1Cre;RosaNotch) or loss (Wnt1Cre;RBP-Jf/f) of Notch signaling in neural crest cells (NCCs) in vivo results in craniofacial, cardiac, and trunk abnormalities. Severe craniofacial malformations are apparent in Wnt1Cre;RosaNotch embryos, while less severe skull abnormalities are evident in Wnt1Cre;RBP-Jf/f mice. Deficient cardiac neural crest migration, resulting in cardiac outflow tract malformations, occurs with increased or decreased Notch signaling in NCCs. Smooth muscle cell differentiation also is impaired in pharyngeal NCC derivatives in both Wnt1Cre;RosaNotch and Wnt1Cre;RBP-Jf/f embryos. Neurogenesis is absent and gliogenesis is increased in the dorsal root ganglia of Wnt1Cre;RosaNotch embryos, while neurogenesis is increased and gliogenesis is decreased in Wnt1Cre;RBP-Jf/f embryos. Together, these studies demonstrate essential cell-autonomous roles for appropriate levels of Notch signaling during NCC migration, proliferation, and differentiation with critical implications in craniofacial, cardiac, and neurogenic development and disease.

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Section: Resultssupporting

confidence: 63%

Notch pathway regulation of neural crest cell development in vivo

Mead

Yutzey

2012

Developmental Dynamics

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“…DLL3 is normally expressed in the developing CNS and has a key role in somitogenesis, the process by which somites (bilaterally paired blocks of mesoderm tissue) form along the anterior–posterior axis of the developing embryo 116,117 . The Notch pathway has been implicated in regulating neuroendocrine versus epithelial-cell differentiation in embryonic lung development 118 and, more recently, in SCLC oncogenesis 12 .…”

Section: Potential Therapeutic Targets In Sclcmentioning

confidence: 99%

Unravelling the biology of SCLC: implications for therapy

et al. 2017

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Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are being clinically tested in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints. Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaetescute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody–drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

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“…These findings and inconsistencies for Dll3 raise the intriguing question of whether Dll3 actually functions in Notch signaling to regulate somitogenesis. Indeed, genetic interactions between Dll3 and Notch1 in mice yield only mild heterozygous mutant phenotypes compared to the strong synergistic interactions reported for known Notch pathway genes (Loomes et al , 2007). Given that during somitogenesis, Wnt and FGF signaling are coordinated with Notch signaling to regulate the periodic expression of a large network of genes (Dequeant et al , 2006), it is tempting to speculate that Dll3 trafficking between the Golgi and plasma membrane might also be regulated during somitogensis.…”

Section: The Dsl Family Outliermentioning

confidence: 99%