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1.
Proc Natl Acad Sci U S A ; 115(38): 9622-9627, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30181276

RESUMO

The brain of mammals differs from that of all other vertebrates, in having a six-layered neocortex that is extensively interconnected within and between hemispheres. Interhemispheric connections are conveyed through the anterior commissure in egg-laying monotremes and marsupials, whereas eutherians evolved a separate commissural tract, the corpus callosum. Although the pattern of interhemispheric connectivity via the corpus callosum is broadly shared across eutherian species, it is not known whether this pattern arose as a consequence of callosal evolution or instead corresponds to a more ancient feature of mammalian brain organization. Here we show that, despite cortical axons using an ancestral commissural route, monotremes and marsupials share features of interhemispheric connectivity with eutherians that likely predate the origin of the corpus callosum. Based on ex vivo magnetic resonance imaging and tractography, we found that connections through the anterior commissure in both fat-tailed dunnarts (Marsupialia) and duck-billed platypus (Monotremata) are spatially segregated according to cortical area topography. Moreover, cell-resolution retrograde and anterograde interhemispheric circuit mapping in dunnarts revealed several features shared with callosal circuits of eutherians. These include the layered organization of commissural neurons and terminals, a broad map of connections between similar (homotopic) regions of each hemisphere, and regions connected to different areas (heterotopic), including hyperconnected hubs along the medial and lateral borders of the cortex, such as the cingulate/motor cortex and claustrum/insula. We therefore propose that an interhemispheric connectome originated in early mammalian ancestors, predating the evolution of the corpus callosum. Because these features have been conserved throughout mammalian evolution, they likely represent key aspects of neocortical organization.


Assuntos
Evolução Biológica , Conectoma , Corpo Caloso/fisiologia , Mamíferos/fisiologia , Neocórtex/fisiologia , Animais , Corpo Caloso/citologia , Corpo Caloso/diagnóstico por imagem , Conjuntos de Dados como Assunto , Imagem de Tensor de Difusão , Feminino , Imagem por Ressonância Magnética , Neocórtex/citologia , Neocórtex/diagnóstico por imagem , Vias Neurais/fisiologia
2.
Curr Opin Neurobiol ; 53: 57-65, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29894898

RESUMO

Long-range projection neurons of the neocortex form the major tracts of the mammalian brain and are crucial for sensory-motor, associative and executive functions. Development of such circuits involves neuronal proliferation, specification and migration, as well as axonal elongation, navigation and targeting, where growing axons encounter multiple guidance cues and integrate these signals to execute guidance decisions. The complexity of axon guidance mechanisms in the formation of long-range neuronal projections has suggested that they might be under control of transcription factors, which are DNA-binding proteins that regulate the expression of downstream genes. Here we discuss recent advances in our understanding of the control of axon guidance by transcriptional regulation, as well as future directions for the elucidation of the mechanisms and pathological relevance of this process.

3.
J Neurosci Methods ; 293: 45-52, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28917658

RESUMO

BACKGROUND: The technique of in utero electroporation has been widely used in eutherians, such as mice and rats, to investigate brain development by selectively manipulating gene expression in specific neuronal populations. A major challenge, however, is that surgery is required to access the embryos, affecting animal survival and limiting the number of times it can be performed within the same litter. NEW METHOD: Marsupials are born at an early stage of brain development as compared to eutherians. Forebrain neurogenesis occurs mostly postnatally, allowing electroporation to be performed while joeys develop attached to the teat. Here we describe the method of in pouch electroporation using the Australian marsupial fat-tailed dunnart (Sminthopsis crassicaudata, Dasyuridae). RESULTS: In pouch electroporation is minimally invasive, quick, successful and anatomically precise. Moreover, as no surgery is required, it can be performed several times in the same individual, and littermates can undergo independent treatments. COMPARISON WITH EXISTING METHOD: As compared to in utero electroporation in rodents, in pouch electroporation in marsupials offers unprecedented opportunities to study brain development in a minimally invasive manner. Continuous access to developing joeys during a protracted period of cortical development allows multiple and independent genetic manipulations to study the interaction of different systems during brain development. CONCLUSIONS: In pouch electroporation in marsupials offers an excellent in vivo assay to study forebrain development and evolution. By combining developmental, functional and comparative approaches, this system offers new avenues to investigate questions of biological and medical relevance, such as the precise mechanisms of brain wiring and the organismic and environmental influences on neural circuit formation.


Assuntos
Eletroporação/métodos , Marsupiais/crescimento & desenvolvimento , Modelos Animais , Prosencéfalo/crescimento & desenvolvimento , Anestesiologia/instrumentação , Animais , Eletrodos , Desenho de Equipamento , Regulação da Expressão Gênica no Desenvolvimento , Vetores Genéticos/administração & dosagem , Imuno-Histoquímica , Microscopia de Fluorescência , Neurônios/citologia , Prosencéfalo/citologia , Análise de Sobrevida
4.
PLoS One ; 12(9): e0184450, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28880940

RESUMO

Most of our understanding of forebrain development comes from research of eutherian mammals, such as rodents, primates, and carnivores. However, as the cerebral cortex forms largely prenatally, observation and manipulation of its development has required invasive and/or ex vivo procedures. Marsupials, on the other hand, are born at comparatively earlier stages of development and most events of forebrain formation occur once attached to the teat, thereby permitting continuous and non-invasive experimental access. Here, we take advantage of this aspect of marsupial biology to establish and characterise a resourceful laboratory model of forebrain development: the fat-tailed dunnart (Sminthopsis crassicaudata), a mouse-sized carnivorous Australian marsupial. We present an anatomical description of the postnatal development of the body, head and brain in dunnarts, and provide a staging system compatible with human and mouse developmental stages. As compared to eutherians, the orofacial region develops earlier in dunnarts, while forebrain development is largely protracted, extending for more than 40 days versus ca. 15 days in mice. We discuss the benefits of fat-tailed dunnarts as laboratory animals in studies of developmental biology, with an emphasis on how their accessibility in the pouch can help address new experimental questions, especially regarding mechanisms of brain development and evolution.


Assuntos
Prosencéfalo Basal/embriologia , Marsupiais/embriologia , Animais , Prosencéfalo Basal/crescimento & desenvolvimento , Prosencéfalo Basal/metabolismo , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Biologia do Desenvolvimento , Humanos , Marsupiais/crescimento & desenvolvimento , Marsupiais/metabolismo , Camundongos
5.
Neural Dev ; 12(1): 9, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28558801

RESUMO

The corpus callosum forms the major interhemispheric connection in the human brain and is unique to eutherian (or placental) mammals. The developmental events associated with the evolutionary emergence of this structure, however, remain poorly understood. A key step in callosal formation is the prior remodeling of the interhemispheric fissure by embryonic astroglial cells, which then subsequently act as a permissive substrate for callosal axons, enabling them to cross the interhemispheric midline. However, whether astroglial-mediated interhemispheric remodeling is unique to eutherian mammals, and thus possibly associated with the phylogenetic origin of the corpus callosum, or instead is a general feature of mammalian brain development, is not yet known. To investigate this, we performed a comparative analysis of interhemispheric remodeling in eutherian and non-eutherian mammals, whose lineages branched off before the evolution of the corpus callosum. Whole brain MRI analyses revealed that the interhemispheric fissure is retained into adulthood in marsupials and monotremes, in contrast to eutherians (mice), in which the fissure is significantly remodeled throughout development. Histological analyses further demonstrated that, while midline astroglia are present in developing marsupials, these cells do not intercalate with one another through the intervening interhemispheric fissure, as they do in developing mice. Thus, developing marsupials do not undergo astroglial-mediated interhemispheric remodeling. As remodeling of the interhemispheric fissure is essential for the subsequent formation of the corpus callosum in eutherians, our data highlight the role of astroglial-mediated interhemispheric remodeling in the evolutionary origin of the corpus callosum.


Assuntos
Astrócitos/fisiologia , Corpo Caloso/crescimento & desenvolvimento , Eutérios/crescimento & desenvolvimento , Telencéfalo/crescimento & desenvolvimento , Animais , Evolução Biológica , Corpo Caloso/anatomia & histologia , Eutérios/anatomia & histologia , Especificidade da Espécie
6.
Nat Genet ; 49(4): 511-514, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28250454

RESUMO

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.


Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Mutação/genética , Receptores de Superfície Celular/genética , Proteínas Supressoras de Tumor/genética , Anormalidades Múltiplas/genética , Encéfalo/patologia , Corpo Caloso/patologia , Receptor DCC , Família , Feminino , Humanos , Masculino , Malformações do Sistema Nervoso/genética , Células-Tronco Neurais/patologia , Penetrância , Fenótipo
7.
Pediatr Cardiol ; 38(2): 324-331, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27872995

RESUMO

The goal of this study is to evaluate whether NT-proBNP plasma levels may help as a screening biomarker for monitoring right ventricular dilatation, pulmonary regurgitation and the onset of heart failure in patients with repaired Tetralogy of Fallot. Our single-centre observational prospective study involved 43 patients (15.1 years, SD = 8) with corrected Tetralogy of Fallot. Data collection included: clinical parameters (electrocardiogram, chest X-ray, NYHA scale, time since last surgery), biochemistry (NT-proBNP levels) and MRI values (ventricular volumetry, pulmonary flow assessment). Mean time since last surgery was 13.5 years (SD = 7.8). There was a statistically significant correlation between the NT-proBNP levels (187.4 pg/ml, SD = 154.9) and right ventricular dilatation for both the right ventricular end-diastolic volume (124.9 ml/m2, SD = 31.2) (Pearson = 0.19, p < 0.01) and end-systolic volume (56.1 ml/m2, SD = 18.8) (Pearson = 0.21, p < 0.01) and also with the pulmonary regurgitation fraction (36.5%, SD = 16, Pearson = 0.12, p < 0.01). No significant correlation was found between NT-proBNP and right ventricular ejection fraction (54.6%, SD = 10.6, Pearson = -0.07), left ventricular ejection fraction (59.9%, SD = 7.1, Pearson = -0.18) or any clinical parameters. The receiver operating curve analysis evidenced that a NT-proBNP cut-off value above 133.2 pg/ml predicted the presence of dilated right ventricular end-diastolic and end-systolic volumes over centile 95 (sensitivity 82 and 83% and specificity 93 and 79%, respectively). In conclusion, in patients with surgically corrected Tetralogy of Fallot, NT-proBNP levels correlate with right ventricular dilatation and the degree of pulmonary regurgitation. Ambulatory determination of NT-proBNP might be an easy, readily available and cost-effective alternative for MRI follow-up evaluation of these patients.


Assuntos
Imagem por Ressonância Magnética , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Insuficiência da Valva Pulmonar/sangue , Volume Sistólico , Tetralogia de Fallot/cirurgia , Disfunção Ventricular Direita/sangue , Adolescente , Biomarcadores/sangue , Criança , Eletrocardiografia , Feminino , Humanos , Masculino , Estudos Prospectivos , Insuficiência da Valva Pulmonar/diagnóstico por imagem , Curva ROC , Disfunção Ventricular Direita/diagnóstico por imagem , Adulto Jovem
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