Hrk/DP5 contributes to the apoptosis of select neuronal populations but is dispensable for haematopoietic cell apoptosis.
The pro-apoptotic BH3-only members of the Bcl2 family, crucial initiators of cell death, are activated by a diverse array of developmental cues or experimentally applied stress stimuli. We have investigated, through gene targeting in mice, the biological roles for the BH3-only family member HRK (also known as DP5) in apoptosis regulation. Hrk gene expression was found to be restricted to cells and tissues of the central and peripheral nervous systems. Sensory neurons from mice lacking Hrk were less sensitive to apoptosis induced by nerve growth factor (NGF) withdrawal, consistent with the induction of Hrk following NGF deprivation. By contrast, cerebellar granule neurons that upregulate Hrk upon transfer to low-K+ medium underwent apoptosis normally under these conditions in the absence of Hrk. Furthermore, loss of Hrk was not sufficient to rescue the neuronal degeneration in lurcher mutant mice. Despite previous reports, no evidence was found for Hrk expression or induction in growth-factor-dependent haematopoietic cell lines following withdrawal of their requisite cytokine, and haematopoietic progenitors lacking HRK died normally in response to cytokine deprivation. These results demonstrate that HRK contributes to apoptosis signalling elicited by trophic factor withdrawal in certain neuronal populations but is dispensable for apoptosis of haematopoietic cells.
Coultas
Leigh
L
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Terzano
Susanna
S
Thomas
Tim
T
Voss
Anne
A
Reid
Kate
K
Stanley
Edouard G
EG
Scott
Clare L
CL
Bouillet
Philippe
P
Bartlett
Perry
P
Ham
Jonathan
J
Adams
Jerry M
JM
Strasser
Andreas
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002531:Cerebellum / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D018390:Gene Targeting; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D020932:Nerve Growth Factor / Q000378:metabolism; D009420:Nervous System / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C107631:Hrk protein, mouse; D009479:Neuropeptides; D020932:Nerve Growth Factor