Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

Abstract

Notch signaling research dates back to more than one hundred years, beginning with the identification of the Notch mutant in the fruit fly Drosophila melanogaster. Since then, research on Notch and related genes in flies has laid the foundation of what we now know as the Notch signaling pathway. In the 1990s, basic biological and biochemical studies of Notch signaling components in mammalian systems, as well as identification of rare mutations in Notch signaling pathway genes in human patients with rare Mendelian diseases or cancer, increased the significance of this pathway in human biology and medicine. In the 21st century, Drosophila and other genetic model organisms continue to play a leading role in understanding basic Notch biology. Furthermore, these model organisms can be used in a translational manner to study underlying mechanisms of Notch-related human diseases and to investigate the function of novel disease associated genes and variants. In this chapter, we first briefly review the major contributions of Drosophila to Notch signaling research, discussing the similarities and differences between the fly and human pathways. Next, we introduce several biological contexts in Drosophila in which Notch signaling has been extensively characterized. Finally, we discuss a number of genetic diseases caused by mutations in genes in the Notch signaling pathway in humans and we expand on how Drosophila can be used to study rare genetic variants associated with these and novel disorders. By combining modern genomics and state-of-the art technologies, Drosophila research is continuing to reveal exciting biology that sheds light onto mechanisms of disease.

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

“…Similarly in mice that have four Notch paralogs (Notch1-4), Notch1 (Koenig et al, 2017;Zhang, Martin, Kelley, & Gridley, 2000) and Notch2 (Witt, Won, Hurez, & Klug, 2003) are also known to be haploinsufficient loci. Considering that the amount of NICD that actively engages in transcription is tightly coupled to the amount of Notch receptors that are synthesized, activated and degraded due to the lack of any signal amplification steps (Salazar & Yamamoto, 2018), even a modest reduction or increase in the amount of receptors can have a significant impact on signal output. Considering that the amount of NICD that actively engages in transcription is tightly coupled to the amount of Notch receptors that are synthesized, activated and degraded due to the lack of any signal amplification steps (Salazar & Yamamoto, 2018), even a modest reduction or increase in the amount of receptors can have a significant impact on signal output.…”

“…Of the four genes encoding Notch receptors in the human genome, variants in NOTCH1, NOTCH2 and NOTCH3 have been associated with rare Mendelian diseases (Louvi & Artavanis-Tsakonas, 2012;Salazar & Yamamoto, 2018), whereas single nucleotide polymorphisms in NOTCH4 have been associated with increased risk of schizophrenia (Wei & Hemmings, 2000) and systemic sclerosis (Cardinale et al, 2016;Zhou et al, 2019) in certain populations (Table 1). Some disease associated human NOTCH variants have been experimentally categorized as pathogenic loss-(LOF) or gain-of-function (GOF) alleles.…”

“…More recently, Notch signaling has been shown to be required in many post-developmental contexts, including tissue homeostasis (Bigas & Porcheri, 2018) and neural physiology (Ables, Breunig, Eisch, & Rakic, 2011). Several features make the canonical Notch signaling pathway unique compared to other evolutionarily conserved core developmental signaling pathways, such as Wnt, Hedgehog, and BMP/TGF-β (Bier, 2005;Salazar & Yamamoto, 2018). For example, while many signaling pathways transmit signals to remotely located cells (paracrine or endocrine signaling), Notch signaling typically occurs between two juxtaposed cells (Hoppe & Greenspan, 1986).…”

“…Furthermore, haploinsufficiency of NOTCH1 in humans has been linked to Adams-Oliver syndrome (OMIM #616028) (Stittrich et al, 2014) and aortic valve diseases (OMIM #109730) (Garg et al, 2005). Considering that the amount of NICD that actively engages in transcription is tightly coupled to the amount of Notch receptors that are synthesized, activated and degraded due to the lack of any signal amplification steps (Salazar & Yamamoto, 2018), even a modest reduction or increase in the amount of receptors can have a significant impact on signal output.…”

“…FLP/FRT based clonal analysis of amorphic N alleles have also revealed the involvement of Notch signaling in various post-embryonic developmental contexts (Salazar & Yamamoto, 2018…”