Abstract
Regulation of innate immune responses and activation of tissue regenerative processes are key elements in the pathophysiology of brain injuries. The promyelocytic leukemia (PML) gene was originally identified on a breakpoint of chromosomal translocation t(15;17) associated with acute PML. We have studied the role of PML protein during acute and regenerative phases after hypoxia–ischemia (HI) in brains of neonatal mice. We found that PML prevents tissue loss and apoptotic cell death selectively in subcortical regions of the brain at early stages after damage. In accordance with this, we revealed that PML is important for microglia activation and production of key inflammatory cytokines such as IL1α, IL1β, IL1RN, CXCL10, CCL12 and TNFα. During the regenerative phase, PML-depleted mice were found to have impaired transformation of transit-amplifying precursors into migratory progenitors. This was accompanied by increased ratios of symmetric versus asymmetric neural progenitor cell divisions during tissue repair and a specific defect in tissue restoration within the striatum 42 days after HI. The data demonstrate a dual role of PML in protection and recovery after brain injury.
Highlights
The promyelocytic leukemia (PML) protein is a tumor suppressor, which is involved in the t(15;17) chromosomal translocation associated with acute promyelocytic leukemia (APL).[1]
To investigate a potential role of PML in protection and regeneration of tissue after injury, we induced cerebral ischemia by permanent occlusion of the left common carotid artery followed by systemic hypoxia in wildtype and PML-depleted mice at postnatal day 9 (P9)
Owing to an inherent variability of brain damage size after HI, these initial experiments were performed by first producing a random number of Pml+/+, Pml+/ − and Pml − / − offspring through heterozygous (Pml+/ − ) mating, and by assessing the HI-induced damage blinded prior to genotyping
Summary
The promyelocytic leukemia (PML) protein is a tumor suppressor, which is involved in the t(15;17) chromosomal translocation associated with acute promyelocytic leukemia (APL).[1]. A hallmark of PML is its ability to organize the formation of chromatin-associated nuclear structures called PML bodies. Following brain injury, such as stroke, multiple cellular and physiological responses, which have the potential of influencing the extent of tissue damage, are activated. During embryonic development of the brain cortex in mouse, PML regulates the transition from radial glia cells to basal progenitors.[18] In addition, PML is required for maintenance and asymmetric commitment of hematopoietic stem cells.[19] A recent study demonstrated a neuroprotective effect of PML in a mouse model of spinocerebellar ataxia 1.11 It is not clear, if PML participate in differentiation and/or tissue morphogenesis after injury in neonatal or adult animals. We identified defects in HI-induced neuroblast production and reduced ratios of asymmetrically committed pairs of transit-amplifying progenitors during brain tissue
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
