Downregulation of the GHRH/GH/IGF-1 axis in a mouse model of Börjeson-Forssman-Lehman Syndrome

McRae, Helen M.; Eccles, Samantha; Whitehead, Lachlan; Alexander, Warren S.; Gécz, Jozef; Thomas, Tim; Voss, Anne K.

doi:10.1242/dev.187021

Cited by 4 publications

(2 citation statements)

References 101 publications

(130 reference statements)

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“…Since a mixed genetic background can be more tolerant of genetic abnormalities and allow further development (e.g. Phf6 42,43 or Tgfb1 mice 44 ) we bred Mcl-1 and Mcl-1 Bcl-xL gene-swap mice on a mixed FVBxBALB/cxC57BL/6 genetic background.…”

Section: One Homozygousmentioning

confidence: 99%

Relative importance of MCL-1’s Anti-Apoptotic versus Non-Apoptotic Functionsin vivo

Brinkmann,

McArthur,

Tee

et al. 2023

Preprint

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MCL1 is an anti-apoptotic member of the BCL2 protein family that ensures cell survival by blocking the intrinsic apoptotic cell death pathway. MCL1 is unique in being essential for early embryonic development and the survival of many cell types, including many cancer cells, which are not affected by the loss of the other anti-apoptotic BCL2 family members. Non-apoptotic functions of MCL1 controlling mitochondrial ATP production and dynamics have been proposed to underlie this unique requirement for MCL1. The relative contributions of the anti-apoptotic versus the non-apoptotic functions of MCL1 in normal physiology have not been addressed. Here we replaced the coding sequence for MCL1 with those for the anti-apoptotic proteins BCLXL, BCL2 or A1. We hypothesised that BCLXL, BCL2 and A1 may substitute for MCL1 in the inhibition of apoptosis, but that they will not be able to replace MCL1's non-apoptotic function. Strikingly, Mcl1^BclxL/BclxL and Mcl1^Bcl2/Bcl2 embryos survived to embryonic day 14.5, greatly surpassing the pre-implantation lethality of Mcl1-/- embryos at E3.5. This demonstrates that the non-apoptotic functions of MCL1 are dispensable for early development. However, at later stages of development and life after birth many cell types, particularly ones with high energy demand, were found to require both the anti-apoptotic and the non-apoptotic functions of MCL1. These findings reveal the relative importance of these distinct functions of MCL1 in physiology, providing important information for basic biology and the advancement of MCL1 inhibitors in cancer therapy.

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Section: One Homozygousmentioning

confidence: 99%

Relative importance of MCL-1’s Anti-Apoptotic versus Non-Apoptotic Functionsin vivo

Brinkmann,

McArthur,

Tee

et al. 2023

Preprint

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“…Germline mutations in Phf6 causes the X-linked intellectual disability (XLID), Börjeson-Forssman-Lehmann syndrome (BFLS), characterized by impairments in cognitive function, epileptic-like seizures, and behavioural disturbances (Lower et al, 2002 ), in addition to endocrine defects (McRae et al, 2020 ). Multiple mutations on the Phf6 gene within the X chromosome have been identified in BFLS patients (Berland et al, 2010 ; Carter et al, 2009 ; Lower et al, 2002 ; Turner et al, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS

Rasool,

Burban,

Sharanek

et al. 2024

EMBO Rep

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The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.

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The Role of PHF6 in Hematopoiesis and Hematologic Malignancies

Eisa¹,

Guo²,

Yang

2022

Stem Cell Rev and Rep

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Downregulation of the GHRH/GH/IGF-1 axis in a mouse model of Börjeson-Forssman-Lehman Syndrome

Cited by 4 publications

References 101 publications

Relative importance of MCL-1’s Anti-Apoptotic versus Non-Apoptotic Functionsin vivo

Relative importance of MCL-1’s Anti-Apoptotic versus Non-Apoptotic Functionsin vivo

PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS

The Role of PHF6 in Hematopoiesis and Hematologic Malignancies

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