The flexed-tail (f) Mutant Mouse: Advancing the Understanding of Expansive Erythropoiesis

Open Access
- Author:
- Lenox, L. E.
- Graduate Program:
- Biochemistry, Microbiology, and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 22, 2005
- Committee Members:
- Robert Paulson, Committee Chair/Co-Chair
Avery August, Committee Member
Pamela Hankey Giblin, Committee Member
Ross Cameron Hardison, Committee Member
Andrew Thomas Henderson, Committee Member - Keywords:
- stress erythropoiesis
extra-medullary erythropoiesis
liver
stress BFU-E
spleen
splicing mutation
Smad5
Madh5
BMP4
flexed-tail
expansive erythropoiesis
acute anemia - Abstract:
- The autosomal, recessive flexed-tail mutant (f/f) mouse has defects at times of expansive erythropoiesis. The phenotype is evident both during development and in the adult. f/f show a transient fetal/neonatal anemia that remits shortly after birth when the main site of hematopoiesis has shifted from the fetal liver to the bone marrow. Adult mice appear normal, but show a delay in their recovery to acute anemia. Analysis of the flexed-tail (f) mutant has shown that the contribution from stress erythroid progenitors resident in the spleen responding to hypoxia-induced BMP4/Madh5 dependent signals is required for the rapid recovery to an acute anemia. The f mutation is a neomorphic mutation of Madh5, with aberrantly spliced transcripts disrupting the normal BMP4 signaling pathway in the spleen following an erythropoietic challenge. Although this splenic contribution to an acute anemia is critical for the rapid return to homeostasis, it is not essential since flexed-tail mice are viable and both humans and mice can survive without a spleen. To further understand the mechanisms of expansive erythropoiesis, we have extended our analysis to splenectomized mice. These mice show altered kinetics of recovery to a phenylhydrazine induced acute anemia with expansive erythropoiesis now seen in the liver. Further, BMP4 is expressed in the liver and liver erythroid progenitors exhibit properties similar to stress BFU-E in the spleen. This work has shown the important role of the BMP4 pathway for regulating expansive erythropoiesis in extra-medullary organs. It has also broadened our appreciation for splicing mutations, the regulations within signaling pathways, and the contribution these pathways make to signaling networks.