title: Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.
abstract: Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD.
authors.affiliation: Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zunino
authors.affiliation: Laboratory of Developmental Neurobiology, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Messina
authors.affiliation: Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Sgadò
authors.affiliation: Laboratory of Cellular and Developmental Neurobiology, Department of Life Sciences, University of Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Baj
authors.affiliation: Laboratory of Developmental Neurobiology, Centre for Integrative Biology, University of Trento, Italy; CNR Institute of Neuroscience, CNR, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Casarosa
authors.affiliation: Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento, Italy; CNR Institute of Neuroscience, CNR, Pisa, Italy. Electronic address: yuri.bozzi@unitn.it.
authors.forename: Y
authors.initials: Y
authors.lastname: Bozzi
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099266:Engrailed 2 Protein
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D020813:Receptor, trkB; D011973:Receptors, LDL; D017475:Receptors, Nerve Growth Factor; D020742:rhoA GTP-Binding Protein; D000099266:Engrailed 2 Protein; C517634:Ngfr protein, mouse
keywords: BDNF; En2; autism; neurotrophin; p75; trkB