RESUMEN
Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.
Asunto(s)
Hidropesía Fetal , Motivo alfa Estéril , Femenino , Humanos , Hidropesía Fetal/diagnóstico por imagen , Hidropesía Fetal/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal/genética , Receptor EphB4/genética , Receptor EphB4/metabolismoRESUMEN
The proper production of gametes over an extended portion of the life of an organism is essential for a high level of fitness. The balance between germline stem cell (GSC) proliferation (self-renewal) and differentiation (production of gametes) must be tightly regulated to ensure proper gamete production and overall fitness. Therefore, organisms have evolved robust regulatory systems to control this balance. Here we discuss the redundancy in the regulatory system that controls the proliferation vs. differentiation balance in the C. elegans hermaphrodite germline, and how this redundancy may contribute to robustness. We focus on the various types of redundancy utilized to regulate this balance, as well as the approaches that have enabled these redundant mechanisms to be uncovered.
RESUMEN
A major event in germline development is the transition from stem/progenitor cells to entry into meiosis and gametogenesis. This transition requires downregulation of mitotic cell cycle activity and upregulation of processes associated with meiosis. We identify the Caenorhabditis elegans SCFPROM-1 E3 ubiquitin-ligase complex as functioning to downregulate mitotic cell cycle protein levels including cyclin E, WAPL-1, and KNL-2 at meiotic entry and, independently, promoting homologous chromosome pairing as a positive regulator of the CHK-2 kinase. SCFPROM-1 is thus a novel regulator of meiotic entry, coordinating downregulation of mitotic cell cycle proteins and promoting homolog pairing. We further show that SCFPROM-1 functions redundantly, in parallel to the previously described GLD-1 and GLD-2 meiotic entry pathways, downstream of and inhibited by GLP-1 Notch signaling, which specifies the stem cell fate. Accordingly, C. elegans employs three post-transcriptional pathways, SCFPROM-1-mediated protein degradation, GLD-1-mediated translational repression, and GLD-2-mediated translational activation, to control and coordinate the initiation of meiotic development.