ABSTRACT
During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.
Subject(s)
Cell Adhesion Molecules, Neuronal/metabolism , DNA-Binding Proteins/physiology , Extracellular Matrix Proteins/metabolism , Gene Expression Regulation, Developmental/physiology , Germ Layers/metabolism , Neocortex/embryology , Animals , Cell Death , Cell Movement/physiology , DNA-Binding Proteins/genetics , Lac Operon/physiology , Mice , Mice, Mutant Strains , Mice, Transgenic , Mutation , Neocortex/abnormalities , Neocortex/growth & development , Nerve Tissue Proteins , Neural Pathways/physiology , Neurons/metabolism , Reelin Protein , Serine Endopeptidases , Synaptic Transmission , T-Box Domain ProteinsABSTRACT
Pallial and subpallial morphological subdivisions of the developing chicken telencephalon were examined by means of gene markers, compared with their expression pattern in the mouse. Nested expression domains of the genes Dlx-2 and Nkx-2.1, plus Pax-6-expressing migrated cells, are characteristic for the mouse subpallium. The genes Pax-6, Tbr-1, and Emx-1 are expressed in the pallium. The pallio-subpallial boundary lies at the interface between the Tbr-1 and Dlx-2 expression domains. Differences in the expression topography of Tbr-1 and Emx-1 suggest the existence of a novel "ventral pallium" subdivision, which is an Emx-1-negative pallial territory intercalated between the striatum and the lateral pallium. Its derivatives in the mouse belong to the claustroamygdaloid complex. Chicken genes homologous to these mouse genes are expressed in topologically comparable patterns during development. The avian subpallium, called "paleostriatum," shows nested Dlx-2 and Nkx-2.1 domains and migrated Pax-6-positive neurons; the avian pallium expresses Pax-6, Tbr-1, and Emx-1 and also contains a distinct Emx-1-negative ventral pallium, formed by the massive domain confusingly called "neostriatum." These expression patterns extend into the septum and the archistriatum, as they do into the mouse septum and amygdala, suggesting that the concepts of pallium and subpallium can be extended to these areas. The similarity of such molecular profiles in the mouse and chicken pallium and subpallium points to common sets of causal determinants. These may underlie similar histogenetic specification processes and field homologies, including some comparable connectivity patterns.
Subject(s)
Body Patterning/genetics , Chick Embryo/metabolism , DNA-Binding Proteins/genetics , Gene Expression Regulation, Developmental/physiology , Homeodomain Proteins/genetics , Mice/embryology , Nuclear Proteins/genetics , Telencephalon/embryology , Transcription Factors/genetics , Age Factors , Animals , Chick Embryo/cytology , Cytoskeletal Proteins , Embryo, Mammalian , Eye Proteins , Mice/anatomy & histology , Mice/metabolism , PAX6 Transcription Factor , Paired Box Transcription Factors , RNA, Messenger/metabolism , RNA-Binding Proteins , Repressor Proteins , T-Box Domain Proteins , Telencephalon/cytology , Telencephalon/metabolism , Thyroid Nuclear Factor 1ABSTRACT
There are at least five murine Dlx genes that are related to the Drosophila Distal-less homeobox gene. The Dlx genes are primarily expressed in the developing forebrain, derivatives of the cranial neural crest and restricted epidermal craniofacial and limb domains. Dlx-2 is required for differentiation of subsets of cranial neural crest and forebrain cells. Previous genomic studies have shown that Dlx-1 and Dlx-2 are linked on mouse chromosome 2, near the HoxD cluster. Here we report a detailed analysis of the nucleotide sequence (approximately 14 kb), organization, and transcription of the murine Dlx-1 and Dlx-2 locus. In addition, we show that Dlx-1 makes multiple sense transcripts and at least one antisense transcript, whereas Dlx-2 makes one major transcript. The sequence of the human Dlx-2 gene is reported and is compared to that of the murine gene. Finally, sequence analysis of the deduced protein sequences reveals several candidate functional domains.
Subject(s)
Homeodomain Proteins/genetics , Sequence Analysis, DNA , Transcription, Genetic , Amino Acid Sequence , Animals , Base Sequence , DNA, Complementary , Humans , Mice , Molecular Sequence Data , Sequence Homology, Amino Acid , Sequence Homology, Nucleic Acid , Transcription FactorsABSTRACT
A 10-week open-label trial of fluvoxamine was conducted for male Vietnam combat veterans with chronic PTSD. Subjects were excluded if they met full current criteria for panic disorder or agoraphobia, and lifetime criteria for psychosis, bipolar disorder, or organic mental syndrome. Repeated MANOVA was performed to determine change over time. Fluvoxamine was well tolerated; side effects were observed primarily early in treatment with headache, insomnia, sedation, and gastrointestinal distress being most frequent. Fluvoxamine was effective for treating the core intrusion, avoidance, and arousal symptoms of PTSD. Large treatment effects were seen by 4-6 weeks, and maintained at 10 weeks. The magnitude of change was greater than has been previously reported for antidepressant treatment of male Vietnam combat veterans with PTSD.
Subject(s)
Combat Disorders/drug therapy , Fluvoxamine/therapeutic use , Ambulatory Care , Combat Disorders/epidemiology , Combat Disorders/psychology , Comorbidity , Depressive Disorder/diagnosis , Depressive Disorder/drug therapy , Depressive Disorder/epidemiology , Humans , Male , Mental Disorders/diagnosis , Mental Disorders/drug therapy , Mental Disorders/epidemiology , Middle Aged , Psychiatric Status Rating Scales , Treatment Outcome , Veterans/psychology , VietnamABSTRACT
The mechanisms that regulate regional specification and evolution of the cerebral cortex are obscure. To this end, we have identified and characterized a novel murine and human gene encoding a putative transcription factor related to the Brachyury (T) gene that is expressed only in postmitotic cells. T-brain-1 (Tbr-1) mRNA is largely restricted to the cerebral cortex, where during embryogenesis it distinguishes domains that we propose may give rise to paleocortex, limbic cortex, and neocortex. Tbr-1 and Id-2 expression in the neocortex have discontinuities that define molecularly distinct neocortical areas. Tbr-1 expression is analyzed in the context of the prosomeric model. Topological maps are proposed for the organization of the dorsal telencephalon.
