Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors.
The Hedgehog (Hh) pathway is essential for normal embryonic development and tissue repair. The role of Hh signaling in hematopoiesis has been studied primarily by modulating the activity of Patched and Smoothened, but results have been conflicting. Some studies demonstrate a requirement for pathway activity in hematopoiesis, whereas others report that it is dispensable. Hh activity converges on the Gli transcription factors, but the specific role of these downstream effectors in hematopoiesis has not been reported. We have analyzed hematopoietic stem cell (HSC) and progenitor function in mice with a homozygous deletion of Gli1 (Gli1(null)). Gli1(null) mice have more long-term HSCs that are more quiescent and show increased engraftment after transplantation. In contrast, myeloid development is adversely affected with decreased in vitro colony formation, decreased in vivo response to granulocyte colony-stimulating factor (G-CSF), and impaired leukocyte recovery after chemotherapy. Levels of the proto-oncogene Cyclin D1 are reduced in Gli1(null) mice and may explain the loss of proliferation seen in HSCs and progenitor cells. These data demonstrate that Gli1 regulates normal and stress hematopoiesis. Moreover, they suggest that Gli1 and Smoothened may not be functionally redundant, and direct GLI1 inhibitors may be needed to effectively block HH/GLI1 activity in human disease.
Merchant
Akil
A
The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Joseph
Giselle
G
Wang
Qiuju
Q
Brennan
Sarah
S
Matsui
William
W
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D007763:Lac Operon; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000166:cytology*; D000072079:Patched Receptors; D000090063:Proto-Oncogene Mas; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000072086:Smoothened Receptor; D013312:Stress, Physiological / Q000502:physiology; D000071676:Zinc Finger Protein GLI1
C530105:Ccnd1 protein, mouse; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000715470:MAS1 protein, human; D000072079:Patched Receptors; D000090063:Proto-Oncogene Mas; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; D019938:Cyclin D1; D016179:Granulocyte Colony-Stimulating Factor