This Week in The Journal

Cellular/Molecular

PARP-1 Activation and Neurotrophins

Leonid Visochek, Ruth A. Steingart, Ina Vulih-Shultzman, Rodica Klein, Esther Priel, Illana Gozes, and Malka Cohen-Armon

(see pages 7420-7428)

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA nicks and thus promotes DNA repair. The addition of ADP-riboses to acidic amino acid residues modifies the chromatin structure and affects DNA transcription and repair. This week, Visochek et al. provide data indicating that neurotrophins can also trigger PARP-1 activation. Brief exposures of cultured cortical neurons to nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT-3) or to two “neuroprotective peptides” [NAP and activity-dependent neurotrophic factor-9 (ADNF-9)] induced increases in PARP-1 activity as measured by ADP-ribose polymer immunoreactivity or PARP-1 auto-polyADP-ribosylation. Pharmacological studies indicated that the signaling cascade involved tropomyosin-related kinase receptor phosphorylation, calcium release from intracellular stores, and calcium-dependent kinases. However, neurotrophin treatment did not produce detectable DNA damage. PARP-1 was also implicated in the NGF-mediated neurite outgrowth in pheochromocytoma 12 cells. The histone H1 was polyADP-ribosylated after neurotrophin treatment, potentially rendering DNA accessible to transcription factors and repair enzymes.

Expression of Olig2 (red) in vimentin+ (green) immature astrocytes cultured from a postnatal day 3 mouse SVZ. See the article by Marshall et al. for details.

Development/Plasticity/Repair

Olig2 and Glial Fate in the SVZ

Christine A. G. Marshall, Bennett G. Novitch, and James E. Goldman

(see pages 7289-7298)

Progenitor cells in the postnatal subventricular zone (SVZ) generate astrocytes and oligodendrocytes as well as the interneurons that travel in the rostral migratory stream (RMS) to the olfactory bulb. Noting that the basic helix-loop-helix transcription factor Olig2 was expressed in glial lineages in the SVZ, Marshall et al. tested whether Olig2 was the determinant of neuronal versus glial fate. In the forebrain, Olig2 was expressed in astrocytes, particularly those with an immature phenotype, as well as oligodendrocytes. The authors used retroviral gene transduction to express Olig2 and green fluorescent protein (GFP) in SVZ cells. GFP-labeled cells migrated into white matter and cerebral cortex but not the RMS. None of the infected cells expressed neuronal markers, and retroviral transduction of GFP alone revealed cells in the RMS and olfactory bulb. A dominant-negative Olig2 construct did not affect neuronal migration, but glial differentiation was disrupted. Thus Olig2 represses the neuronal fate but is required for glial fates.

Behavioral/Systems/Cognitive

Blocking Caspases in Neuropathic Pain

Joachim Scholz, Daniel C. Broom, Dong-Ho Youn, Charles D. Mills, Tatsuro Kohno, Marc R. Suter, Kimberly A. Moore, Isabelle Decosterd, Richard E. Coggeshall, and Clifford J. Woolf

(see pages 7317-7323)

Neuropathic pain after peripheral nerve injuries may involve decreased inhibition in the spinal cord. This week, Scholz et al. examine slowly accumulating apoptotic cell death in the superficial dorsal horn after several types of partial peripheral nerve injury in rats. A month after the injury, 20% of dorsal horn neurons were lost and GABAergic IPSCs were also decreased in lamina II neurons, consistent with loss of interneurons. Block of afferent activity reduced cell death, indicating that ectopic afferent activity in the injured nerve underlies the prolonged time course of cell death after the injury. Intrathecal treatment with a caspase inhibitor prevented the loss of interneurons and IPSCs and reduced the behavioral hypersensitivity to innocuous touch and cold stimuli. The results suggest that neuroprotection may be a useful strategy for treatment of neuropathic pain.

Neurobiology of Disease

The Spectrum of FGF Signaling on Oligodendrocytes

Dale Fortin, Eran Rom, Haijun Sun, Avner Yayon, and Rashmi Bansal

(see pages 7470-7479)

Orchestrating the activities of a large family is no easy task. However, this week Fortin et al. try to sort out the diverse actions of the fibroblast growth factor-2 (FGF-2) family and its receptors on oligodendrocyte (OL) development. There are 22 members of the FGF-2 family, 18 of which are expressed in the brain. Although FGF-2 activates all four FGF receptors (FGFRs), other family members are more selective. The authors used specific FGF ligands and receptor blocking antibodies to examine purified populations of progenitor OLs or mature OLs. FGF-8 and FGF-17 inhibited final differentiation of OL progenitors through activation of FGFR3, whereas FGF-9 via FGFR3 triggered an increase in process outgrowth of differentiated OLs. FGF-18 activated FGFR2 and FGFR3 and thus had actions on both progenitors and differentiated OLs. Perhaps of interest in myelin pathogenesis, FGF-2 led to proliferation of OL progenitors but caused mature OLs to reenter the cell cycle and downregulate myelin proteins.