Genetic Background Modifies Inner Ear and Eye Phenotypes of Jag1 Heterozygous Mice

Abstract

Mice heterozygous for missense mutations of the Notch ligand Jagged1 ( Jag1) exhibit head-shaking behavior indicative of an inner ear vestibular defect. In contrast, mice heterozygous for a targeted deletion of the Jag1 gene ( Jag1 del1 ) do not demonstrate obvious head-shaking behavior. To determine whether the differences in inner ear phenotypes were due to the types of Jag1 mutations or to differences in genetic background, we crossed Jag1 del1 heterozygous mice onto the same genetic background as the missense mutants. This analysis revealed that variation of the Jag1 mutant inner ear phenotype is caused by genetic background differences and is not due to the type of Jag1 mutation. Genome scans of N2 backcross mice identified a significant modifier locus on chromosome 7, as well as a suggestive locus on chromosome 14. We also analyzed modifiers of an eye defect in Jag1 del1 heterozygous mice from this same cross.

Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates

“…The Jag1 ligand is also expressed in the cochlear duct as the first hair cells differentiate (Figure 1C), and later in supporting cells (Morrison et al, 1999; Woods et al, 2004). Jag1 heterozygous mice also have increased inner hair cells (Kiernan et al, 2007; Moayedi et al, 2014), and we observed a similar phenotype of duplication of inner hair cells and inner phalangeal cells in Jag1 heterozygous mice (Figure 3A,B). We also confirmed that loss of both Lfng and Mfng led to a reduction in Notch signaling directly, by comparing N1ICD staining in Lfng;Mfng embryos to wild type controls (Figure 4A).…”

The developmental biology of genetic Notch disorders

“…Interestingly, similar to other Jag1 phenotypes (Kiernan et al, 2007), the biliary phenotype is highly background dependent, as backcrossing of Jag1 +/− into a C57BL/6J background results in defects similar to those observed in Jag1/Notch2 double heterozygotes (Thakurdas et al, 2016). This study also revealed that Jag1 stability is negatively regulated by O-glucosyltransferase 1 (POGLUT1, also known as Rumi), and that reduced Rumi levels in Jag1 +/− /Rumi +/− animals rescue the biliary phenotype of Jag1-deficient animals.…”

“…The Jag2 sm phenotype is recessive and homozygous lethal in several pups after birth. Interestingly, Hans Grüneberg observed that several phenotypes are dependent on genetic background, which, as mentioned previously, is also the case for Jag1 (Kiernan et al, 2007). Furthermore, sm/sm mice often have twisted or kinked tails, which can be indicative of neural tube defects, although in this case appears to be related to epidermal hyperplasia.…”

“…The systemic knockout of Jag1 is embryonic lethal in mice at ∼E11.5 due to defects in angiogenesis of the embryonic and yolk sac vasculature (Kiernan et al, 2007;Xue et al, 1999). Likewise, homozygous Notch2 knockout mice die at ∼E10.5, displaying widespread apoptosis (Hamada et al, 1999;McCright et al, 2006).…”

The Candidate Splicing Factor Sfswap Regulates Growth and Patterning of Inner Ear Sensory Organs

“…Most of these compound mutants (10/14) exhibited semicircular canal truncations, but neither Sfswap Tg/Tg nor Jag1 +/− mutants have canal truncations on this genetic background (Figure 6A). Jag1 +/− mutants are known to have variations in semicircular canal defects depending on the genetic background [33]. To test if this is the case for the FVB/N background on which our Sfswap Tg mice were maintained, Jag1 +/− mice were crossed one and two generations to wild-type FVB/N mice.…”