Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

Gao, Christine W; Lin, Wan-Ying; Riddle, Ryan C.; Kushwaha, Priyanka; Boukas, Leandros; Björnsson, Hans T.; Hansen, Kasper D.; Fahrner, Jill A.

doi:10.1101/2023.06.23.546270

Cited by 4 publications

(1 citation statement)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In support of these hypotheses, functional investigations have shown that single nucleotide variants in the WD40 domain of EED abolish binding to EZH2 in vitro (Denisenko et al, 1998). Mouse models encoding pathogenic EZH2 missense variants, which are predicted to result in loss of function of the PRC2 complex, phenocopy Weaver syndrome and cause excess osteogenesis and skeletal overgrowth (Gao et al, 2023). In this study, we show that loss of Eed after neural crest induction causes the opposite phenotype, resulting in craniofacial hypoplasia due to impairments in osteogenesis, mesenchymal cell proliferation, and mesenchymal stem cell differentiation.…”

Section: Discussionmentioning

confidence: 97%

Eedcontrols craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest

Casey-Clyde,

Liu,

Serrano

et al. 2024

Preprint

View full text Add to dashboard Cite

The histone methyltransferase Polycomb repressive complex 2 (PRC2) is required for specification of the neural crest, and mis-regulation of the neural crest can cause severe congenital malformations. PRC2 is required for induction of the neural crest, but the embryonic, cellular, and molecular consequences of PRC2 activity after neural crest induction are incompletely understood. Here we show that Eed, a core subunit of PRC2, is required for craniofacial osteoblast differentiation and mesenchymal proliferation after induction of the neural crest. Integrating mouse genetics with single-cell RNA sequencing, our results reveal that conditional knockout of Eed after neural crest cell induction causes severe craniofacial hypoplasia, impaired craniofacial osteogenesis, and attenuated craniofacial mesenchymal cell proliferation that is first evident in post-migratory neural crest cell populations. We show that Eed drives mesenchymal differentiation and proliferation in vivo and in primary craniofacial cell cultures by regulating diverse transcription factor programs that are required for specification of post-migratory neural crest cells. These data enhance understanding of epigenetic mechanisms that underlie craniofacial development, and shed light on the embryonic, cellular, and molecular drivers of rare congenital syndromes in humans.

show abstract

Section: Discussionmentioning

confidence: 97%

Eedcontrols craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest

Casey-Clyde,

Liu,

Serrano

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1

Gao,

Lin,

Riddle

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Growth retardation is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth retardation in a mouse model of KS1 and further established that aKmt2d-/-chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth retardation in a mouse model of KS2,Kdm6atm1d/+. We show thatKdm6atm1d/+mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure.Kdm6atm1d/+growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found thatKdm6a-/-cells undergo premature, enhanced differentiation towards chondrocytes compared toKdm6a+/+controls. RNA-seq showed thatKdm6a-/-cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously onKmt2d-/-,Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression betweenKmt2d-/-andKdm6a-/-at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.

show abstract

Eed controls craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest

Casey-Clyde,

Liu,

Serrano

et al. 2024

Preprint

View full text Add to dashboard Cite

The histone methyltransferase Polycomb repressive complex 2 (PRC2) is required for specification of the neural crest, and mis-regulation of neural crest development can cause severe congenital malformations. PRC2 is necessary for neural crest induction, but the embryonic, cellular, and molecular consequences of PRC2 activity after neural crest induction are incompletely understood. Here we show that Eed , a core subunit of PRC2, is required for craniofacial osteoblast differentiation and mesenchymal proliferation after induction of the neural crest. Integrating mouse genetics with single-cell RNA sequencing, our results reveal that conditional knockout of Eed after neural crest cell induction causes severe craniofacial hypoplasia, impaired craniofacial osteogenesis, and attenuated craniofacial mesenchymal cell proliferation that is first evident in post-migratory neural crest cell populations. We show that Eed drives mesenchymal differentiation and proliferation in vivo and in primary craniofacial cell cultures by regulating diverse transcription factor programs that are required for specification of post-migratory neural crest cells. These data enhance understanding of epigenetic mechanisms that underlie craniofacial development, and shed light on the embryonic, cellular, and molecular drivers of rare congenital syndromes in humans.

show abstract

Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

Cited by 4 publications

References 91 publications

Eedcontrols craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest

Eedcontrols craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest

Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1

Eed controls craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest

Contact Info

Product

Resources

About