A SOX17-PDGFB signaling axis regulates aortic root development

Lu, Pengfei; Wang, Ping; Wu, Bingruo; Wang, Yidong; Liu, Yang; Cheng, W. S.; Feng, Xuemei; Yuan, Xinchun; Atteya, Miriam M; Ferro, Haleigh; Sugi, Yukiko; Rydquist, Grant; Esmaily, Mahdi; Butcher, Jonathan T.; Chang, Ching-Pin; Lenz, Jack; Zheng, Deyou; Zhou, Bin

doi:10.1038/s41467-022-31815-1

Cited by 8 publications

(2 citation statements)

References 111 publications

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“…The non‐coronary leaflet is derived from the intercalated leaflet swellings (sometimes called intercalated valve cushions); it has been proposed that it is a lack of these structures that results in the two‐sinus type of BAV (Anderson et al., 2014 ). Absence (or dysplasia) of the non‐coronary leaflet has been associated with SOX17‐PDGRB signalling (Lu et al., 2022 ). The other heart with BAV was seen in an E15.5 homozygote; the aortic valve appeared to be of the fused type, with the right and non‐coronary leaflets fused (Figure 3d ).…”

Section: Discussionmentioning

confidence: 99%

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

Waheed‐Ullah,

Wilsdon,

Abbad

et al. 2024

Journal of Anatomy

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Congenital heart disease (CHD) is the most common congenital anomaly, with an overall incidence of approximately 1% in the United Kingdom. Exome sequencing in large CHD cohorts has been performed to provide insights into the genetic aetiology of CHD. This includes a study of 1891 probands by our group in collaboration with others, which identified three novel genes—CDK13, PRKD1, and CHD4, in patients with syndromic CHD. PRKD1 encodes a serine/threonine protein kinase, which is important in a variety of fundamental cellular functions. Individuals with a heterozygous mutation in PRKD1 may have facial dysmorphism, ectodermal dysplasia and may have CHDs such as pulmonary stenosis, atrioventricular septal defects, coarctation of the aorta and bicuspid aortic valve. To obtain a greater appreciation for the role that this essential protein kinase plays in cardiogenesis and CHD, we have analysed a Prkd1 transgenic mouse model (Prkd1em1) carrying deletion of exon 2, causing loss of function. High‐resolution episcopic microscopy affords detailed morphological 3D analysis of the developing heart and provides evidence for an essential role of Prkd1 in both normal cardiac development and CHD. We show that homozygous deletion of Prkd1 is associated with complex forms of CHD such as atrioventricular septal defects, and bicuspid aortic and pulmonary valves, and is lethal. Even in heterozygotes, cardiac differences occur. However, given that 97% of Prkd1 heterozygous mice display normal heart development, it is likely that one normal allele is sufficient, with the defects seen most likely to represent sporadic events. Moreover, mRNA and protein expression levels were investigated by RT‐qPCR and western immunoblotting, respectively. A significant reduction in Prkd1 mRNA levels was seen in homozygotes, but not heterozygotes, compared to WT littermates. While a trend towards lower PRKD1 protein expression was seen in the heterozygotes, the difference was only significant in the homozygotes. There was no compensation by the related Prkd2 and Prkd3 at transcript level, as evidenced by RT‐qPCR. Overall, we demonstrate a vital role of Prkd1 in heart development and the aetiology of CHD.

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Section: Discussionmentioning

confidence: 99%

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

Waheed‐Ullah,

Wilsdon,

Abbad

et al. 2024

Journal of Anatomy

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“…Here, our scRNA-seq analysis revealed that Sox17 -null RT had reduced expression of several growth factor genes such as Tgfb2, Rspo1 , and Pdgfa , together with decreasing tendencies in Fgf and Wnt family ligands. Tgfb2 and Pdgfa are known to be involved in valve formation of the heat and aorta 45 , 46 , while they can contribute to the activation of PI3K-AKT signaling 47 , 48 which is characteristic of the SV Sertoli cells. Similarly, FGF9 activates AKT in Sertoli cells 25 .…”

Section: Discussionmentioning

confidence: 99%

SOX17-positive rete testis epithelium is required for Sertoli valve formation and normal spermiogenesis in the male mouse

et al. 2022

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Seminiferous tubules (STs) in the mammalian testes are connected to the rete testis (RT) via a Sertoli valve (SV). Spermatozoa produced in the STs are released into the tubular luminal fluid and passively transported through the SV into the RT. However, the physiological functions of the RT and SV remain unclear. Here, we identified the expression of Sox17 in RT epithelia. The SV valve was disrupted before puberty in RT-specific Sox17 conditional knockout (Sox17-cKO) male mice. This induced a backflow of RT fluid into the STs, which caused aberrant detachment of immature spermatids. RT of Sox17-cKO mice had reduced expression levels of various growth factor genes, which presumably support SV formation. When transplanted next to the Sox17+ RT, Sertoli cells of Sox17-cKO mice reconstructed the SV and supported proper spermiogenesis in the STs. This study highlights the novel and unexpected modulatory roles of the RT in SV valve formation and spermatogenesis in mouse testes, as a downstream action of Sox17.

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Quantitative 4D imaging of biomechanical regulation of ventricular growth and maturation

Cho

Poon

Zhu

et al. 2023

Current Opinion in Biomedical Engineering

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A SOX17-PDGFB signaling axis regulates aortic root development

Cited by 8 publications

References 111 publications

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

SOX17-positive rete testis epithelium is required for Sertoli valve formation and normal spermiogenesis in the male mouse

Quantitative 4D imaging of biomechanical regulation of ventricular growth and maturation

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