Browsing by Author "Ibanez, Carlos F."

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    Cell-autonomous role of GFRα1 in the development of olfactory bulb GABAergic interneurons
    (The Company of Biologists, 2018-05-18) Zechel, Sabrina; Fernandez-Suarez, Diana; Ibanez, Carlos F.
    GFRα1, a receptor for glial cell line-derived neurotrophic factor (GDNF), is critical for the development of the main olfactory system. The olfactory bulb (OB) of Gfra1 knockout mice shows significant reductions in the number of olfactory sensory neurons, mitral and tufted cells, as well as all major classes of OB GABAergic interneurons. However, the latter do not express significant levels of GFRα1, leaving the mechanism of action of GFRα1 in OB interneuron development unexplained. Here we report that GFRα1 is highly expressed in the precursor cells that give rise to all major classes of OB interneurons, but is downregulated as these neurons mature. Conditional ablation of GFRα1 in embryonic GABAergic cells recapitulated the cell losses observed in global Gfra1 knockouts at birth. GFRα1 was also required for the sustained generation and allocation of OB interneurons in adulthood. Conditional loss of GFRα1 altered the migratory behaviour of neuroblasts along the rostral migratory stream (RMS) as well as RMS glial tunnel formation. Together, these data indicate that GFRα1 functions cellautonomously in subpopulations of OB interneuron precursors to regulate their generation and allocation in the mammalian OB.
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    Death domain signaling by disulfide-linked dimers of the p75 neurotrophin receptor mediates neuronal death in the CNS
    (Society for Neuroscience, 2016-05-18) Tanaka, Kazuhiro; Kelly, Claire E.; Goh, Ket Yin; Lim, Kim Buay; Ibanez, Carlos F.
    The p75 neurotrophin receptor (p75NTR) mediates neuronal death in response to neural insults by activating a caspase apoptotic pathway. The oligomeric state and activation mechanism that enable p75NTR to mediate these effects have recently been called into question. Here, we have investigated mutant mice lacking the p75NTR death domain (DD) or a highly conserved transmembrane (TM) cysteine residue (Cys 259) implicated in receptor dimerization and activation. Neuronal death induced by proneurotrophins or epileptic seizures was assessed and compared with responses in p75NTR knock-out mice and wild-type animals. Proneurotrophins induced apoptosis of cultured hippocampal and cortical neurons from wild-type mice, but mutant neurons lacking p75NTR, only the p75NTRDD, or just Cys 259 were all equally resistant to proneurotrophin-induced neuronal death. Homo-FRET anisotropy experiments demonstrated that both NGF and proNGF induce conformational changes in p75NTR that are dependent on the TM cysteine. In vivo, neuronal death induced by pilocarpine-mediated seizures was significantly reduced in the hippocampus and somatosensory, piriform, and entorhinal cortices of all three strains of p75NTR mutant mice. Interestingly, the levels of protection observed in mice lacking the DD or only Cys 259were identical tothose of p75NTR knock-out mice eventhoughthe Cys 259mutant differedfromthe wild-type receptorin only one amino acid residue.We conclude that, both in vitro and in vivo, neuronal death induced by p75NTR requires the DD and TM Cys 259, supporting the physiological relevance of DD signaling by disulfide-linked dimers of p75NTR in the CNS.