The glycine cleavage system (GCS) is a complex located on the mitochondrial membrane that is responsible for regulating glycine levels and contributing one-carbon units to folate metabolism. Congenital mutations in GCS components, such as glycine decarboxylase (gldc), cause an elevation in glycine levels and the rare disease, nonketotic hyperglycinemia (NKH). NKH patients suffer from pleiotropic symptoms including seizures, lethargy, mental retardation, and early death. Therefore, it is imperative to fully elucidate the pathological effects of gldc dysfunction and glycine accumulation during development. Here, we describe a zebrafish model of gldc deficiency that recapitulates phenotypes seen in humans and mice. gldc deficient embryos displayed impaired fluid homeostasis suggesting renal abnormalities, as well as aberrant craniofacial morphology and neural development defects. Whole mount in situ hybridization (WISH) revealed that gldc transcripts were highly expressed in the embryonic kidney, as seen in mouse and human repository data, and that formation of several nephron segments was disrupted in gldc deficient embryos, including proximal and distal tubule populations. These kidney defects were caused by alterations in renal progenitor populations, revealing that the proper function of Gldc is essential for the patterning of this organ. Additionally, further analysis of the urogenital tract revealed altered collecting duct and cloaca morphology in gldc deficient embryos. Finally, to gain insight into the molecular mechanisms underlying these disruptions, we examined the effects of exogenous glycine treatment and observed analogous renal and cloacal defects. Taken together, these studies indicate for the first time that gldc function serves an essential role in regulating renal progenitor development by modulating glycine levels.
A kidney organoid is a three-dimensional (3D) cellular aggregate grown from stem cells in vitro that undergoes self-organization, recapitulating aspects of normal renal development to produce nephron structures that resemble the native kidney organ. These miniature kidney-like structures can also be derived from primary patient cells and thus provide simplified context to observe how mutations in kidney-disease-associated genes affect organogenesis and physiological function. In the past several years, advances in kidney organoid technologies have achieved the formation of renal organoids with enhanced numbers of specialized cell types, less heterogeneity, and more architectural complexity. Microfluidic bioreactor culture devices, single-cell transcriptomics, and bioinformatic analyses have accelerated the development of more sophisticated renal organoids and tailored them to become increasingly amenable to high-throughput experimentation. However, many significant challenges remain in realizing the use of kidney organoids for renal replacement therapies. This review presents an overview of the renal organoid field and selected highlights of recent cutting-edge kidney organoid research with a focus on embryonic development, modeling renal disease, and personalized drug screening.
Glycine is a simple amino acid that is vital to the proper functioning of the body, but its roles during ontogeny are not well understood. Glycine levels are precisely regulated through the glycine cleavage system (GCS), a complex molecular machine that produces one‐carbon units for later metabolism and folate production. Elevated glycine levels due to congenital mutations in GCS components, such as glycine dehydrogenase (gldc), cause devastating human birth defects and the rare disease nonketotic hyperglycinemia (NKH). The exact pathological implications of glycine accumulation are unknown, but NKH patients suffer from pleiotropic symptoms including seizures, apnea, lethargy, severe mental retardation, and early death. Animal models utilizing mice and zebrafish have shown increased ventriculomegaly and motor dysfunction in gldc deficient animals, but have not analyzed organogenesis. Here, we have utilized zebrafish as a genetic platform to explore the roles of gldc during early development. Whole mount in situ hybridization revealed that gldc transcripts were highly expressed in multiple tissues, including the central nervous system and embryonic kidney, recapitulating both mouse and human expression studies. gldc deficiency caused hydrocephalus and pericardial edema, suggesting defects in brain and renal ontogeny. Elevated apoptosis was detected in locations within the brain, kidney, and cloaca. Furthermore, formation of nephron cell populations in the kidney was disrupted in gldc deficient embryos, where the proximal straight tubule was increased at the expense of the distal tubule. Morphological and expression studies revealed severe alterations in brain patterning and morphogenesis as well. Taken together, these studies indicate that gldc has essential roles during early development and have revealed novel functions for pattern formation and cell survival in tissues such as the brain and kidney. Our evidence further emphasizes the zebrafish as a faithful model to examine NKH. Ongoing work with the zebrafish model is poised to expand our medical understanding about the developmental defects consequent to NKH and can be used to perform chemical screens to identify potential therapeutic interventions.
characgteristics were recorded and they were then followed to check for polyp recurrence by transvaginal ultrasound scan 3 months,6 months,9 months and 12 months after the operation. RESULTS: One hundred and one cases for multiple EP group and 81 single EP cases were enrolled. Patients' ages were lower in the multiple group than in the single group(34.4AE5.7 versus 36.75AE6.4,P<0.05). Other baseline parameters were all comparable between two groups. After one year of follow up, 46% (95%CI, 34% -57% )of patients from multiple EP group had polyp recurrence, while only 13%(95%CI, 5%-22%) of patients recur in the single EP group, P<0.05. Furthermore ,the polyp recurrence rates from multiple EP group were also significantly higher than single EP group in each follow-up time intervals with 9.8% vs.1.3% after 3 months, 20% vs. 4.1% after 6 months and 33.1%vs.11.5% after 9 months.COX regression analysis revealed that multiple polyps (HR3.5, 95%CI 1.4-8.5, P<0.01), endometriosis (HR2.4,95%CI 1.1-5.4, P<0.05) and history of polypectomy (HR2.2,95%CI 1.0-4.6, P<0.05) were significantly predictors for polyp recurrence after polypectomy, while patients' age, BMI, gravida, parity, polycystic ovary syndrome and leiomyoma were not associated with polyp recurrence.CONCLUSIONS: Multiple polyps, endometriosis and history of EPs were associated with a greater potential of polyp recurrence after hysteroscopic polypectomy. Patients with excessive growth of multiple EPs were much more vulnerable to polyp recurrence than those with single polyp, indicating that these two different types of polyps may possibly arise by a different etiology and pathogenesis.
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