Regulation of murine normal and stress-induced erythropoiesis by Desert Hedgehog

Abstract

The function of Hedgehog signaling in hematopoiesis is controversial, with different experimental systems giving opposing results. Here we examined the role of Desert Hedgehog (Dhh) in the regulation of murine erythropoiesis. Dhh is one of 3 mammalian Hedgehog family proteins. Dhh is essential for testis development and Schwann cell function. We show, by analysis of Dhh-deficient mice, that Dhh negatively regulates multiple stages of erythrocyte differentiation. In Dhh-deficient bone marrow, the common myeloid progenitor (CMP) population was increased, but differentiation from CMP to granulocyte/macrophage progenitor was decreased, and the mature granulocyte population was decreased, compared with wild-type (WT). In contrast, differentiation from CMP to megakaryocyte/ erythrocyte progenitor was increased, and the megakaryocyte/erythrocyte progenitor population was increased. In addition, we found that erythroblast populations were Dhh-responsive in vitro and ex vivo and that Dhh negatively regulated erythroblast differentiation. In Dhh-deficient spleen and bone marrow, BFU-Es and erythroblast populations were increased compared with WT. During recovery of hematopoiesis after irradiation, and under conditions of stress-induced erythropoiesis, erythrocyte differentiation was accelerated in both spleen and bone mar- IntroductionThe Hedgehog (Hh) family of secreted intercellular signaling proteins are essential for the development of many tissues during embryogenesis and are also involved in the homeostasis of adult tissues, including skin, gut, bone, and thymus. [1][2][3][4] Their role in the regulation of hematopoiesis, however, has proved controversial, with different experimental models supporting opposing interpretations. [5][6][7][8][9][10][11][12][13] Here, we investigate erythropoiesis in Desert Hh (Dhh)-null adult mice and show that Dhh is a negative regulator of normal and stress-induced erythropoiesis.There are 3 mammalian Hh proteins, with distinct patterns of expression and functions: Sonic Hh (Shh), Indian Hh (Ihh), and Dhh. Shh and Ihh are each essential for mouse development, whereas Dhh mutant mice are healthy and appear normal, although males are infertile. [14][15][16] Shh is most pleiotrophic of the family members and is essential for development of many tissues and organs, including brain, heart, lungs, limbs, and thymus. 16,17 Ihh has some overlapping functions with Shh and is essential for bone differentiation 15,18,19 and the regulation of thymocyte differentiation. 2 In contrast, the functions of Dhh seem to be more limited to testis development and Schwann cell function, hence the viability and lack of obvious phenotype of Dhh-deficient animals. 14,20 The Hh proteins share a common signaling pathway, which is initiated when the Hh ligand binds to its cell-surface receptor Patched (Ptch). This releases Ptch's inhibition of the signaling molecule Smoothened (Smo), allowing transduction of the Hh signal into the cell, and activation of the Hh-responsive transcription factors, glioblastoma-ass...

In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors

“…Interestingly, Dhh is expressed at significantly lower levels and observed later during recovery, which is consistent with its role as a negative regulator. 32 Furthermore, the expression of Epo in the kidney is not induced until day 6, which correlates with the initial increase in CD34 …”

The kinesin motor protein Kif7 is required for T-cell development and normal MHC expression on thymic epithelial cells (TEC) in the thymus

“…Genotyping of Kif7 mutant mice by PCR was performed as described [37] with primers neo (5′-GCAGCGCATCGCCTTCTATCG-3′), exon 2 (5′-GGCGGGACCGACACTTTGGG-3′), and intron 2 (5′-CACCTGACATGGAGTGCTGACC-3′), generating a 302 bp product in WT and 197 bp product in knockout allele.…”

β-Thalassemia and Polycythemia vera: Targeting chronic stress erythropoiesis

“…While Desert hedgehog (Dhh) has been reported to be a negative, i.e. inhibiting, regulator of the proliferation and differentiation of steady-state and stress progenitors, it has been demonstrated that some hedgehog signaling is required for ensuring sensitivity of stress progenitors to the BMP4-induced stress response (Lau et al, 2012, Perry et al, 2009). …”