Lymphopenia in Ednrb-deficient rat was strongly modified by genetic background

Abstract

The endothelin signaling pathway plays an important role in the migration, proliferation, and differentiation of neural crest cells. Mutations in the gene encoding the endothelin receptor type B (EDNRB) cause three symptoms: aganglionosis, pigmented disorder and hearing loss. In addition, the Ednrb null mice show abnormal splenic microarchitecture with lymphopenia. In this study, we examined whether similar phenotypes are reproduced in three Ednrb-null rat strains that we established previously. AGH-Ednrb sl/sl strain showed a low white blood cell count, significant size reduction and abnormal microarchitecture of spleen. Thymus displayed a marked reduction in the size, but maintained a normal CD4/CD8 ratio. In contrast, splenic cellularity was reduced to < 15%, and splenic B and T cell numbers were reduced, showing a splenic lymphopenia. Interestingly, Ednrb-null rats in the LE and F344 genetic background did not show these abnormalities. These data show that proper T and B cell development is dependent on the endothelin signaling pathway, however, modifier gene(s) might be differentially expressed in these strain to modulate or compensate for the effect of the Ednrb deficiency.The endothelin receptor type B (EDNRB) is a G protein-coupled receptor that activates a phosphatidylinositol-calcium second messenger system. The receptor interacts with a family of ligands known as endothelins to regulate several critical biological processes, including the development and function of blood vessels, the production of certain hormones, and the stimulation of cell growth and division (9). Endothelin 3 is one of the proteins that interacts with EDNRB. During embryonic development, endothelin 3/EDNRB interaction plays an important role in the migration, proliferation, and differentiation of neural crest cells (2,8). These cells migrate from the neural tube to the specific regions in the embryo, where they give rise to many different types of cells including the neurons and glia of the enteric ganglia, melanocytes, facial cartilage and bone, and chromaffin cells of the adrenal medulla (7). Mutations in the EDNRB gene caused Waardenburg-Shah Syndrome 4 (3), which is characterized by changes in skin, hair, and eye coloring, hearing loss, and the Hirschsprung disease that causes severe constipation or intestinal blockage. We established the AGH-Ednrb sl/sl rat harboring null allele of the Ednrb gene (5). Homozygous mutant rats showed hearing loss with pigmentation disturbance in addition to Hirschsprung disease, which is an authentic model of Waardenburg-Shah Syndrome 4. The Ednrb null mice show abnormal splenic microarchitecture with lymphopenia, and relative reduction of B cells compared to T cells (4). To test whether similar phenotypes are produced in three rat strains bearing null mutation of Ednrb, we examined the abnormality in the thymus and spleen. Ge-

Enterocolitis causes profound lymphoid depletion in endothelin receptor B‐ and endothelin 3‐null mouse models of Hirschsprung‐associated enterocolitis

“…Recently, Dang et al reported that the AGH-Ednrb sl/sl rat model of HSCR showed lymphoid depletion with markedly reduced spleen weight and total splenic cell count of less than 15% of wild-type AGH rats, with severe reduction of B cells, and CD4 and CD8 T cells [29]. The AGH-Ednrb sl/sl rat also had significantly reduced thymic weight and cell number, with no change in the CD4/CD8 ratio when studied at only 8 days of life, but otherwise very similar to the murine models in our study.…”

Novel Insights into the Pathogenesis of Hirschsprung's-associated Enterocolitis

“…[ 54 ] However, Dang et al . [ 55 ] found that genetic background was related to different immune state. Abnormal splenic microarchitecture with lymphopenia was observed in AGH-Ednrb−/− rats, but not detected in LE and F344 genetic background Ednrb−/− rats.…”

Neural Crest Cells Contribute an Astrocyte-like Glial Population to the Spleen

“…Additionally, small splenic size has been noted in the conventional EdnrB deletion model1724. Based on this, we hypothesized that there may be a direct contribution of NCC to the spleen.…”