Subtle Changes in the Levels of BCL-2 Proteins Cause Severe Craniofacial Abnormalities

Grabow, Stephanie; Kueh, Andrew J.; Ke, Francine; Vanyai, Hannah K.; Sheikh, Bilal N.; Dengler, Michael A.; Chiang, William; Eccles, Samantha; Smyth, Ian; Jones, Lynelle K.; Sauvage, Frédéric J. de; Scott, Marc; Whitehead, Lachlan; Voss, Anne K.; Strasser, Andreas

doi:10.1016/j.celrep.2018.08.048

Cited by 37 publications

(34 citation statements)

References 55 publications

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“…We have previously shown that the body weight of E19.5 Mcl-1 +/− pups was significantly lower than WT littermates 6 , and observed that Mcl-1 +/− mice developed normally and survive into late adulthood 6 . These findings are consistent with the current observations and suggest that the reduction in MCL-1 either alone or in combination with a reduction in BCL-2 likely affects numerous aspects of organismal development and growth.…”

Section: Discussionmentioning

confidence: 93%

“…Earlier work aimed to determine the roles of various BCL-2 family members in cancer and embryonic development through the study of single, as well as multiple gene knockout mice 3,6 . Such studies revealed that systemic loss of either pro-survival MCL-1 7 or BCL-XL 8 resulted in embryonic lethality, while the loss of BCL-2 gave rise to runty animals that succumbed to polycystic kidney disease at a young age (4-7 weeks post-birth) 9,10 .…”

Section: Introductionmentioning

confidence: 99%

“…We examined the overlapping roles of different pro-survival BCL-2 family members by generating Mcl-1 +/− Bcl-x +/− , Mcl-1 +/− Bcl-2 +/− and Bcl-x +/− Bcl-2 +/− mice. While the combined loss of single alleles of Mcl-1 and Bcl-x disrupted normal embryogenesis and gave rise to animals with severe craniofacial abnormalities, with most dying soon after or even before birth, these defects were prevented by the deletion of a single allele of the pro-apoptotic BH3-only protein, BIM 6 . In contrast, Mcl1 +/− Bcl-2 +/− and Bcl-x +/− Bcl-2 +/− mice appeared grossly normal and were long-lived 6 .…”

Section: Introductionmentioning

confidence: 99%

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Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice

Lancaster

Grabow

et al. 2020

Cell Death Dis

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The intrinsic apoptotic pathway is controlled by the BCL-2 family of proteins, which exhibit either a pro-death or prosurvival function. Gene knockout studies revealed that different pro-survival BCL-2 proteins are critical for the survival of distinct cell types, although overlapping functions amongst such proteins have also been identified. In the process of studying mice lacking single alleles of Mcl-1 (Mcl-1 +/−), Bcl-2 (Bcl-2 +/−), or both in combination (Mcl-1 +/− Bcl-2 +/−), we observed that Mcl-1 +/− Bcl-2 +/− mice weighed less when compared with their wild-type littermates as they aged. Body composition analysis demonstrated that while fat mass was similar to wild-type controls, lean mass was significantly reduced in Mcl-1 +/− , Bcl-2 +/− , and, most strikingly in Mcl-1 +/− Bcl-2 +/− mice. The weights of several tissues including the heart, tibialis anterior, and kidney were likewise reduced in Mcl-1 +/− Bcl-2 +/− mice. When lean mass and specific tissue weights were expressed relative to body weight, these differences were no longer significant, indicating that that Mcl-1 +/− Bcl-2 +/− mice, and to a lesser extent Mcl-1 +/− and Bcl-2 +/− mice, are smaller than their wild-type counterparts. Consistently, the anal-naso length was reduced in Mcl-1 +/− Bcl-2 +/− mice. While minor reductions in size were observed in female Mcl-1 +/− Bcl-2 +/− mice, these effects were most prominent in males. Notably, Mcl-1 +/− Bcl-2 +/− males had markedly smaller testes even after accounting for differences in body weight. Collectively, these data reveal that combined loss of a single allele of Mcl-1 and Bcl-2, while not overtly impairing organismal development, leads to a reduction in animal size.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice

Lancaster

Grabow

et al. 2020

Cell Death Dis

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“…The BH3-only protein BIM can bind to and repress the function of several pro-survival BCL-2 family members and therefore plays a critical role in initiating apoptotic pathway in multiple cell types (Chipuk and Green, 2008;Czabotar et al, 2014;Youle and Strasser, 2008). A recent report showed that mutations in the pro-survival genes Mcl-1 and Bcl-x leads to severe holoprosencephaly, which can be corrected by further loss of Bim, indicating that cell survival and cell death are finely balanced during development (Grabow et al, 2018). To investigate the role of cell survival and determine if a reduction of Bim levels can rescue craniofacial defects in Fgfr1 cKO/cKO ; Fgfr2 cKO/cKO mutants, we first compared Fgfr1 cKO/cKO ; Fgfr2 cKO/+ ; Bim +/mutants with control Fgfr1 cKO/cKO ; Fgfr2 cKO/+ embryos at E17.5.…”

Section: Increased Apoptosis Is Observed In Mutant Facial Primordiamentioning

confidence: 99%

FGF signaling in development beyond canonical pathways

Ray

Mazot

Catela

et al. 2020

Preprint

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FGFs are key developmental regulators which engage a signal transduction cascade through receptor tyrosine kinases, typically involving ERK1/2, PI3K/AKT, and other effectors. However, it remains unknown if all FGF activities depend on kinase activity or these canonical signal transduction cascades. To address these questions, we generated allelic series of knock-in Fgfr1 and Fgfr2 mouse strains, carrying point mutations that disrupt binding of signaling effectors to the receptors, alone or in combination. We also produced a kinase dead allele of Fgfr2 which broadly phenocopies the null mutant. When interrogated in cranial neural crest cells, point mutations in either receptor revealed discrete functions for signaling pathways in specific craniofacial contexts, but failed to recapitulate the single or double null mutant phenotypes even in their most extensive combination. Furthermore, we found that together these signaling mutations abrogated the established FGF-induced signal transduction pathways, yet certain FGF functions such as cell-matrix and cell-cell adhesion remained unaffected. Our studies establish combinatorial roles of both Fgfr1 and Fgfr2 in development and identify novel kinase-dependent cell adhesion properties of FGF receptors, independent of well-established roles in intracellular signaling.

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“…Activator BH3-proteins can also be sequestered by antiapoptotic Bcl-2 proteins, but are released by the sensitizer subgroup of BH3-only proteins, such as Bad, which compete for binding 12 . Thus, variation in the expression and interaction of the different Bcl-2 family subgroups can set the level of priming, subtle changes in which have profound implications for processes such as embryonic development 13 .…”

Section: Introductionmentioning

confidence: 99%

BioID based proteomic analysis of the Bid interactome identifies novel proteins involved in cell cycle dependent apoptotic priming

Pedley

King

Mallikarjun

et al. 2019

Preprint

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Apoptotic priming refers to the proximity of cells to outer mitochondrial membrane permeabilisation (MOMP), the point of apoptosis commitment. Variations in priming are important for how both normal and cancer cells respond to chemotherapeutic agents. Individual cells adjust their level of priming in response to changing circumstances, such as genomic damage. How changes in apoptotic priming are dynamically coordinated by Bcl-2 proteins remains unclear. We have previously demonstrated that the Bcl-2 protein, Bid, becomes phosphorylated as cell enter mitosis, increasing priming. To understand how cells coordinate dynamic changes in priming, we have performed an unbiased proximity biotinylation (BioID) screen using Bid as bait. This identified several potential regulatory proteins outside the core Bcl-2 family. In particular we found VDAC2 to be essential for Bid phosphorylation dependent changes in apoptotic priming during mitosis. These results show the importance of dissecting the wider Bcl-2 interactome, and identify a key scaffold protein coordinating dynamic changes in single cell priming.

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Subtle Changes in the Levels of BCL-2 Proteins Cause Severe Craniofacial Abnormalities

Cited by 37 publications

References 55 publications

Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice

Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice

FGF signaling in development beyond canonical pathways

BioID based proteomic analysis of the Bid interactome identifies novel proteins involved in cell cycle dependent apoptotic priming

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