The developmental biology of genetic Notch disorders

Abstract

Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies inDrosophila

“…Since N nd-3 is hemizygous/homozygous viable and these animals only exhibit a mild defect in wing margin (wing notching) and wing vein (thickening of the ends of wing veins, referred to as "wing delta" which is also seen upon Delta haploinsufficiency) development, it is considered as a weak hypomorphic (mild LOF) allele. Another interesting but unexplained aspect of CADASIL alleles is that although NOTCH3 has 34 EGFr, most of the variants linked to this disease are found in EGFr-1-5 (corresponding to EGFr-1-6 in Drosophila Notch which has 36 EGFr) (Joutel et al, 1997;Masek & Andersson, 2017 (Lindsley & Zimm, 1992). Interestingly, the majority of NOTCH3 variants that are linked to CADASIL are alleles that decrease (5 cysteine/EGFr) or increase (7 cysteine/EGFr) the number of cysteine residues in EGFr, and N Mcd5 mutations (Joutel et al, 1996) (Baudrimont, Dubas, Joutel, Tournier-Lasserve, & Bousser, 1993;Ishiko et al, 2006).…”

Effects of Notch glycosylation on health and diseases

“…Mutations in genes encoding for Notch-related proteins, such as Notch receptors, ligands, and glycosyltransferases, result in a variety of congenital disorders (Mašek & Andersson, 2017). For example, the mutations in NOTCH2 or JAGGED1 cause the Alagille syndrome, an autosomal dominant disorder characterized by abnormal development of the liver, eyes, kidney, pancreas, heart, vascular system, skeleton, and/or face (Li et al, 1997;McDaniell et al, 2006).…”

Extracellular Vesicles: Decoding a New Language for Cellular Communication in Early Embryonic Development

“…The Notch signaling pathway controls many important developmental events, such as cell differentiation decision, polarity, and patterning (reviewed by Mašek and Andersson, 2017). Notch is a transmembrane protein whose intracellular domain is cleaved upon cell contact after binding to Delta.…”