A mouse model of adult-onset anaemia due to erythropoietin deficiency

Yamazaki, Shun; Souma, Tomokazu; Hirano, Ikuo; Pan, Xiaoqing; Minegishi, Naoko; Suzuki, Norio; Yamamoto, Masayuki

doi:10.1038/ncomms2950

Cited by 70 publications

(133 citation statements)

References 57 publications

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“…39), these results are consistent with NEP cell-derived Epo activating the primitive erythropoiesis at E9.0. We also found that the Cish gene, one of the early response genes to Epo stimulation 2,21 , was dramatically induced at E9.0 (Fig. 6e).…”

Section: Articlementioning

confidence: 72%

“…To elucidate the contribution of Epo to primitive erythropoiesis, we analysed an Epo-knockout (Epo-KO or Epo À / À ) mouse line ( Supplementary Fig. S1) 20,21 . No apparent abnormality was observed in Epo-KO embryos at E8.5 (5-9 somite pair stages (sp); Fig.…”

Section: Resultsmentioning

confidence: 99%

“…REP cells express the interstitial fibroblast marker CD73 and neuronal markers, such as microtubule-associated protein 2 and neurofilament light polypeptide [19][20][21]44,45 . Neural crest-derived cells distribute in the interstitial space of renal tubules in adult mice 45 .…”

Section: Discussionmentioning

confidence: 99%

“…We previously established the Epo-deficient mouse line in which enhanced GFP complementary DNA (BD Biosciences) was inserted into the Epo locus 20,21 . The Epo-GFP transgenic mouse lines and the Gata1-HRD-GFP transgenic mouse line were also previously generated 6,15,19,22,34 .…”

Section: Methodsmentioning

confidence: 99%

“…We have identified renal Epo-producing (REP) cells in the interstitial space of the kidney [19][20][21] . REP cells secrete Epo into the bloodstream where it acts as an endocrine factor for bone marrow EPs 6,22 .…”

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confidence: 99%

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Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

et al. 2013

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Erythropoietin (Epo) supports both primitive erythropoiesis in the yolk sac and definitive erythropoiesis in the fetal liver and bone marrow. Although definitive erythropoiesis requires kidney-and liver-secreted Epo, it is unclear which cells produce Epo for primitive erythropoiesis. Here we find neural Epo-producing (NEP) cells in mid-gestational stage embryos using mouse lines that express green fluorescent protein (GFP) under the Epo gene regulation. In these mice, GFP is expressed exclusively in a subpopulation of neural and neural crest cells at embryonic day 9.0 when Epo-deficient embryos exhibit abnormalities in primitive erythropoiesis. The GFP-positive NEP cells express Epo mRNA and the ex vivo culture of embryonic day 8.5 neural tubes results in the secretion of Epo, which is able to induce the proliferation and differentiation of yolk sac-derived erythroid cells. These results thus suggest that NEP cells secrete Epo and might support the development of primitive erythropoiesis.

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Section: Articlementioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

et al. 2013

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Novel role of cystic fibrosis transmembrane conductance regulator in maintaining adult mouse olfactory neuronal homeostasis

Pfister

Weber

Härtig

et al. 2014

J of Comparative Neurology

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The olfactory epithelium (OE) of mice deficient in cystic fibrosis transmembrane conductance regulator (CFTR) exhibits ion transport deficiencies reported in human CF airways, as well as progressive neuronal loss, suggesting defects in olfactory neuron homeostasis. Microvillar cells, a specialized OE cell-subtype, have been implicated in maintaining tissue homeostasis. These cells are endowed with a PLCβ2/IP3 R3/TRPC6 signal transduction pathway modulating release of neuropeptide Y (NPY), which stimulates OE stem cell activity. It is unknown, however, whether microvillar cells also mediate the deficits observed in CFTR-null mice. Here we show that Cftr mRNA in mouse OE is exclusively localized in microvillar cells and CFTR immunofluorescence is coassociated with the scaffolding protein NHERF-1 and PLCβ2 in microvilli. In CFTR-null mice, PLCβ2 was undetectable, NHERF-1 mislocalized, and IP3 R3 more intensely stained, along with increased levels of NPY, suggesting profound alteration of the PLCβ2/IP3 R3 signaling pathway. In addition, basal olfactory neuron homeostasis was altered, shown by increased progenitor cell proliferation, differentiation, and apoptosis and by reduced regenerative capacity following methimazole-induced neurodegeneration. The importance of CFTR in microvillar cells was further underscored by decreased thickness of the OE mucus layer and increased numbers of immune cells within this tissue in CFTR-KO mice. Finally, we observed enhanced immune responses to an acute viral-like infection, as well as hyper-responsiveness to chemical and physical stimuli applied intranasally. Taken together, these data strengthen the notion that microvillar cells in the OE play a key role in maintaining tissue homeostasis and identify several mechanisms underlying this regulation through the multiple functions of CFTR.

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Establishment of a Diamond‐Blackfan anemia like model in zebrafish

Ling,

Wu,

Liu

et al. 2024

Developmental Dynamics

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BackgroundAnemia is defined as a lack of erythrocytes, low hemoglobin levels, or abnormal erythrocyte morphology. Diamond‐Blackfan anemia (DBA) is a rare and severe congenital hypoplastic anemia that occurs due to the dominant inheritance of a ribosomal protein gene mutation. Even rarer is a case described as Diamond‐Blackfan anemia like (DBAL), which occurs due to a loss‐of‐function EPO mutation recessive inheritance. The effective cures for DBAL are bone marrow transfusion and treatment with erythropoiesis‐stimulating agents (ESAs). To effectively manage the condition, construction of DBAL models to identify new medical methods or screen drugs are necessary.ResultsHere, an epoa‐deficient mutant zebrafish called epoaszy8 was generated to model DBAL. The epoa‐deficiency in zebrafish caused developmental defects in erythroid cells, leading to severe congenital anemia. Using the DBAL model, we validated a loss‐of‐function EPO mutation using an in vivo functional analysis and explored the ability of ESAs to alleviate congenital anemia.ConclusionsTogether, our study demonstrated that epoa deficiency in zebrafish leads to a phenotype resembling DBAL. The DBAL zebrafish model was found to be beneficial for the in vivo assessment of patient‐derived EPO variants with unclear implications and for devising potential therapeutic approaches for DBAL.

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A mouse model of adult-onset anaemia due to erythropoietin deficiency

Cited by 70 publications

References 57 publications

Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

Novel role of cystic fibrosis transmembrane conductance regulator in maintaining adult mouse olfactory neuronal homeostasis

Establishment of a Diamond‐Blackfan anemia like model in zebrafish

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