Strain-specific modifier genes of<i>Cecr2</i>-associated exencephaly in mice: genetic analysis and identification of differentially expressed candidate genes

Kooistra, Megan; Leduc, Renee Y.M.; Dawe, Christine E.; Fairbridge, Nicholas A.; Rasmussen, Jay; Man, Julie H.Y.; Bujold, Mattea; Juriloff, D. M.; King-Jones, Kirst; McDermid, Heather E.

doi:10.1152/physiolgenomics.00124.2011

Cited by 13 publications

(10 citation statements)

References 28 publications

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“…Our data also suggest that atrophins might function with Fat cadherins in vertebrates, as in flies, to regulate planar polarity. Finally, we have seen strong inbred genetic background effects in Fat loss-of-function phenotypes, not only in the cranial neural tube, which generally shows a clear strain dependency of defects (Banting et al, 2005;Choi and Klingensmith, 2009;Colmenares et al, 2002;Ikeda et al, 1999;Kaneko et al, 2007;Kooistra et al, 2012;Sah et al, 1995;Sang et al, 2011;Stottmann et al, 2006;Wright et al, 2007), but also in other tissues. These as yet unidentified modifiers might impact the distinct phenotypic readouts caused by loss of Fat, such as defective Fat-planar polarity signaling versus Fat-Hippo signaling.…”

Section: Discussionmentioning

confidence: 81%

Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity

et al. 2012

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SUMMARYThe atypical cadherin fat (ft) was originally discovered as a tumor suppressor in Drosophila and later shown to regulate a form of tissue patterning known as planar polarity. In mammals, four ft homologs have been identified (Fat1-4). Recently, we demonstrated that Fat4 plays a role in vertebrate planar polarity. Fat4 has the highest homology to ft, whereas other Fat family members are homologous to the second ft-like gene, ft2. Genetic studies in flies and mice imply significant functional differences between the two groups of Fat cadherins. Here, we demonstrate that Fat family proteins act both synergistically and antagonistically to influence multiple aspects of tissue morphogenesis. We find that Fat1 and Fat4 cooperate during mouse development to control renal tubular elongation, cochlear extension, cranial neural tube formation and patterning of outer hair cells in the cochlea. Similarly, Fat3 and Fat4 synergize to drive vertebral arch fusion at the dorsal midline during caudal vertebra morphogenesis. We provide evidence that these effects depend on conserved interactions with planar polarity signaling components. In flies, the transcriptional co-repressor Atrophin (Atro) physically interacts with Ft and acts as a component of Fat signaling for planar polarity. We find that the mammalian orthologs of atro, Atn1 and Atn2l, modulate Fat4 activity during vertebral arch fusion and renal tubular elongation, respectively. Moreover, Fat4 morphogenetic defects are enhanced by mutations in Vangl2, a 'core' planar cell polarity gene. These studies highlight the wide range and complexity of Fat activities and suggest that a Fat-Atrophin interaction is a conserved element of planar polarity signaling.

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Section: Discussionmentioning

confidence: 81%

Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity

et al. 2012

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“…A reduction in exencephaly penetrance from 54.1% to ∼36.1 to 41.6% in all three sub‐interval congenic lines, as well as similar reductions in the MOD 5/31, MOD 5/+, and MOD 31/+ combinations (Fig. ; Table ), suggests that there are at least two modifiers within the chromosome 19 modifier region, one of which would be within the MOD 4 sub‐region, and the other within the MOD 31 sub‐region (Kooistra et al, , Leduc, unpublished). We then focused on the overlap between MOD 5 and MOD 31 to determine if there was additivity between the two presumptive modifier loci.…”

Section: Ntds and Mouse Modifiersmentioning

confidence: 86%

“…Exencephaly penetrance analyses in subinterval congenic strains MOD 4, MOD 5, MOD 31, which divide chromosome 19 into four subregions (brackets on the right), suggest that FVB/N contains at least two nonadditive modifier loci. The MOD lines were created by crossing BALB/c and FVB/N strains and selecting for specific FVB/N subregions of chromosome 19 in four further BALB/c backcrosses, then introducing the Cecr2 GT45Bic allele (Kooistra et al, ). MOD 5/+ was generated by crossing MOD 5 to BALB/c and the same was done to generate MOD 31/+.…”

Section: Ntds and Mouse Modifiersmentioning

confidence: 99%

“…The penetrance data shown here represents a combination of two experiments done several years apart. MOD 4 and MOD 5/31 are from the original experiment (Kooistra et al, ) and MOD 5/+ and MOD 31/+ are from a more recent unpublished experiment. MOD 5 and MOD 31 represent the combined data from both experiments (the two data sets for each line were not significantly different and, therefore, combined).…”

Section: Ntds and Mouse Modifiersmentioning

confidence: 99%

“…In addition, the two backgrounds revealed differences in expressivity. MOD 4 and MOD 5/31 are from the original experiment (Kooistra et al, 2012) and MOD 5/1 and MOD 31/1 are from a more recent unpublished experiment.…”

Section: Cecr2 and Modifier Loci On Mouse Chromosome 19mentioning

confidence: 99%

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Genetic backgrounds and modifier genes of NTD mouse models: An opportunity for greater understanding of the multifactorial etiology of neural tube defects

Leduc

Singh

McDermid

2017

Birth Defects Research

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Neurulation, the early embryonic process of forming the presumptive brain and spinal cord, is highly complex and involves hundreds of genes in multiple genetic pathways. Mice have long served as a genetic model for studying human neurulation, and the resulting neural tube defects (NTDs) that arise when neurulation is disrupted. Because mice appear to show mostly single gene inheritance for NTDs and humans show multifactorial inheritance, mice sometimes have been characterized as a simpler model for the identification and study of NTD genes. But are they a simple model? When viewed on different genetic backgrounds, many genes show significant variation in the penetrance and expressivity of NTD phenotypes, suggesting the presence of modifier loci that interact with the target gene to affect the phenotypic expression. Looking at mutations on different genetic backgrounds provides us with an opportunity to explore these complex genetic interactions, which are likely to better emulate similar processes in human neurulation. Here, we review NTD genes known to show strain-specific phenotypic variation. We focus particularly on the gene Cecr2, which is studied using both a hypomorphic and a presumptive null mutation on two different backgrounds: one susceptible (BALB/c) and one resistant (FVB/N) to NTDs. This strain difference has led to a search for genetic modifiers within a region on murine chromosome 19. Understanding how genetic variants alter the phenotypic outcome in NTD mouse models will help to direct future studies in humans, particularly now that more genome wide sequencing approaches are being used. Birth Defects Research 109:140-152, 2017. © 2016 Wiley Periodicals, Inc.

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Mouse as a model for multifactorial inheritance of neural tube defects

Zohn

2012

Birth Defects Research Pt C

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Neural tube defects (NTDs) such as spina bifida and anencephaly are some of the most common structural birth defects found in humans. These defects occur due to failures of neurulation, a process where the flat neural plate rolls into a tube. In spite of their prevalence, the causes of NTDs are poorly understood. The multifactorial threshold model best describes the pattern of inheritance of NTDs where multiple undefined gene variants interact with environmental factors to cause an NTD. To date, mouse models have implicated a multitude of genes as required for neurulation, providing a mechanistic understanding of the cellular and molecular pathways that control neurulation. However, the majority of these mouse models exhibit NTDs with a Mendelian pattern of inheritance. Still, many examples of multifactorial inheritance have been demonstrated in mouse models of NTDs. These include null and hypomorphic alleles of neurulation genes that interact in a complex fashion with other genetic mutations or environmental factors to cause NTDs. These models have implicated several genes and pathways for testing as candidates for the genetic basis of NTDs in humans, resulting in identification of putative pathogenic mutations in some patients. Mouse models also provide an experimental paradigm to gain a mechanistic understanding of the environmental factors that influence NTD occurrence, such as folic acid and maternal diabetes, and have led to the discovery of additional preventative nutritional supplements such as inositol. This review provides examples of how multifactorial inheritance of NTDs can be modeled in the mouse.

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Strain-specific modifier genes ofCecr2-associated exencephaly in mice: genetic analysis and identification of differentially expressed candidate genes

Cited by 13 publications

References 28 publications

Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity

Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity

Genetic backgrounds and modifier genes of NTD mouse models: An opportunity for greater understanding of the multifactorial etiology of neural tube defects

Mouse as a model for multifactorial inheritance of neural tube defects

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