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1.
Cell ; 139(3): 597-609, 2009 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-19879845

RESUMO

Extrinsic signals controlling generation of neocortical neurons during embryonic life have been difficult to identify. In this study we demonstrate that the dorsal forebrain meninges communicate with the adjacent radial glial endfeet and influence cortical development. We took advantage of Foxc1 mutant mice with defects in forebrain meningeal formation. Foxc1 dosage and loss of meninges correlated with a dramatic reduction in both neuron and intermediate progenitor production and elongation of the neuroepithelium. Several types of experiments demonstrate that retinoic acid (RA) is the key component of this secreted activity. In addition, Rdh10- and Raldh2-expressing cells in the dorsal meninges were either reduced or absent in the Foxc1 mutants, and Rdh10 mutants had a cortical phenotype similar to the Foxc1 null mutants. Lastly, in utero RA treatment rescued the cortical phenotype in Foxc1 mutants. These results establish RA as a potent, meningeal-derived cue required for successful corticogenesis.


Assuntos
Meninges/metabolismo , Neurogênese , Neurônios/citologia , Tretinoína/metabolismo , Animais , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Técnicas In Vitro , Camundongos , Prosencéfalo/citologia , Prosencéfalo/metabolismo
2.
Genesis ; 50(5): 415-23, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22162152

RESUMO

Retinoic acid (RA) signaling is necessary for proper patterning and morphogenesis during embryonic development. Tissue-specific RA signaling requires precise spatial and temporal synthesis of RA from retinal by retinaldehyde dehydrogenases (Raldh) and the conversion of retinol to retinal by retinol dehydrogenases (Rdh) of the short-chain dehydrogenase/reducatase gene family (SDR). The SDR, retinol dehydrogenase 10 (RDH10), is a major contributor to retinal biosynthesis during mid-gestation. We have identified a missense mutation in the Rdh10 gene (Rdh10(m366Asp) ) using an N-ethyl-N-nitrosourea-induced forward genetic screen that result in reduced RA levels and signaling during embryonic development. Rdh10(m366Asp) mutant embryos have unique phenotypes, such as edema, a massive midline facial cleft, and neurogenesis defects in the forebrain, that will allow the identification of novel RA functions.


Assuntos
Oxirredutases do Álcool/genética , Mutação de Sentido Incorreto , Transdução de Sinais , Tretinoína/metabolismo , Animais , Clonagem Molecular , Camundongos
3.
Dev Biol ; 340(1): 41-53, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20096683

RESUMO

Precise control of neuronal migration is essential for proper function of the brain. Taking a forward genetic screen, we isolated a mutant mouse with defects in interneuron migration. By genetic mapping, we identified a frame shift mutation in the pericentrin (Pcnt) gene. The Pcnt gene encodes a large centrosomal coiled-coil protein that has been implicated in schizophrenia. Recently, frame shift and premature termination mutations in the pericentrin (PCNT) gene were identified in individuals with Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD II), both of which are characterized by greatly reduced body and brain sizes. The mouse Pcnt mutant shares features with the human syndromes in its overall growth retardation and reduced brain size. We found that dorsal lateral ganglionic eminence (dLGE)-derived olfactory bulb interneurons are severely affected and distributed abnormally in the rostral forebrain in the mutant. Furthermore, mutant interneurons exhibit abnormal migration behavior and RNA interference knockdown of Pcnt impairs cell migration along the rostal migratory stream (RMS) into the olfactory bulb. These findings indicate that pericentrin is required for proper migration of olfactory bulb interneurons and provide a developmental basis for association of pericentrin function with interneuron defects in human schizophrenia.


Assuntos
Antígenos/genética , Movimento Celular/fisiologia , Interneurônios/citologia , Mutação , Bulbo Olfatório/metabolismo , Animais , Centrossomo/metabolismo , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
PLoS Biol ; 2(8): E219, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15314648

RESUMO

Although the mechanisms that regulate development of the cerebral cortex have begun to emerge, in large part through the analysis of mutant mice (Boncinelli et al. 2000; Molnar and Hannan 2000; Walsh and Goffinet 2000), many questions remain unanswered. To provide resources for further dissecting cortical development, we have carried out a focused screen for recessive mutations that disrupt cortical development. One aim of the screen was to identify mutants that disrupt the tangential migration of interneurons into the cortex. At the same time, we also screened for mutations that altered the growth or morphology of the cerebral cortex. We report here the identification of thirteen mutants with defects in aspects of cortical development ranging from the establishment of epithelial polarity to the invasion of thalamocortical axons. Among the collection are three novel alleles of genes for which mutant alleles had already been used to explore forebrain development, and four mutants with defects in interneuron migration. The mutants that we describe here will aid in deciphering the molecules and mechanisms that regulate cortical development. Our results also highlight the utility of focused screens in the mouse, in addition to the large-scale and broadly targeted screens that are being carried out at mutagenesis centers.


Assuntos
Córtex Cerebral/patologia , Modelos Genéticos , Mutação , Alelos , Animais , Axônios , Movimento Celular , Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Drosophila , Etilnitrosoureia/farmacologia , Extremidades/patologia , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica , Interneurônios/citologia , Óperon Lac , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese Sítio-Dirigida , Neurônios/metabolismo , Fatores de Transcrição de Fator Regulador X , Análise de Sequência de DNA , Fatores de Transcrição/genética , Transgenes , Proteínas Supressoras de Tumor/fisiologia
5.
Elife ; 42015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26705332

RESUMO

In mammals, the neocortical layout consists of few modality-specific primary sensory areas and a multitude of higher order ones. Abnormal layout of cortical areas may disrupt sensory function and behavior. Developmental genetic mechanisms specify primary areas, but mechanisms influencing higher order area properties are unknown. By exploiting gain-of and loss-of function mouse models of the transcription factor Emx2, we have generated bi-directional changes in primary visual cortex size in vivo and have used it as a model to show a novel and prominent function for genetic mechanisms regulating primary visual area size and also proportionally dictating the sizes of surrounding higher order visual areas. This finding redefines the role for intrinsic genetic mechanisms to concomitantly specify and scale primary and related higher order sensory areas in a linear fashion.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Córtex Visual/anatomia & histologia , Córtex Visual/fisiologia , Animais , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Visão Ocular
6.
PLoS One ; 8(7): e69333, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23935987

RESUMO

Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting.


Assuntos
Cromossomos Humanos Par 6 , Fenda Labial/genética , Fissura Palatina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Proteínas Nucleares/genética , Translocação Genética , Alelos , Sequência de Aminoácidos , Animais , Pontos de Quebra do Cromossomo , Mapeamento Cromossômico , Fenda Labial/patologia , Fissura Palatina/patologia , Feminino , Homozigoto , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética
7.
Sci Signal ; 2(95): ra70, 2009 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-19887680

RESUMO

Regulatory factor X (Rfx) homologs regulate the transcription of genes necessary for ciliogenesis in invertebrates and vertebrates. Primary cilia are necessary for Hedgehog signaling and regulation of the activity of the transcriptional regulators known as Gli proteins, which are targets of Hedgehog signaling. Here, we describe an Rfx4(L298P) mouse mutant with distinct dorsoventral patterning defects in the ventral spinal cord and telencephalon due to aberrant Sonic hedgehog (Shh) signaling and Gli3 activity. We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4, and the decrease in its expression in the developing telencephalon and spinal cord of Rfx4(L298P) mutants correlates with defects in patterning and cilia formation. Our data indicate that Rfx4 is a regionally specific transcriptional regulator of ciliogenesis and thus is also a regionally specific modulator of Shh signaling during development of the central nervous system.


Assuntos
Cílios , Proteínas de Ligação a DNA/fisiologia , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Fatores de Transcrição/fisiologia , Animais , Sistema Nervoso Central/crescimento & desenvolvimento , Proteínas de Ligação a DNA/genética , Camundongos , Mutação , Fatores de Transcrição de Fator Regulador X , Medula Espinal , Telencéfalo , Fatores de Transcrição/genética , Transcrição Gênica
8.
Proc Natl Acad Sci U S A ; 104(35): 14002-7, 2007 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-17715063

RESUMO

We report the identification of a hypomorphic mouse allele for Foxc1 (Foxc1(hith)) that survives into adulthood revealing previously unknown roles for Foxc1 in development of the skull and cerebral cortex. This line of mice was recovered in a forward genetic screen using ENU mutagenesis to identify mutants with cortical defects. In the hith allele a missense mutation substitutes a Leu for a conserved Phe at amino acid 107, leading to destabilization of the protein without substantially altering transcriptional activity. Embryonic and postnatal histological analyses indicate that diminished Foxc1 protein expression in all three layers of meningeal cells in Foxc1(hith/hith) mice contributes to the cortical and skull defects in mutant mice and that the prominent phenotypes appear as the meninges differentiate into pia, arachnoid, and dura. Careful analysis of the cortical phenotypes shows that Foxc1(hith/hith) mice display detachment of radial glial endfeet, marginal zone heterotopias, and cortical dyslamination. These abnormalities have some features resembling defects in type 2 (cobblestone) lissencephaly or congenital muscular dystrophies but appear later in corticogenesis because of the delay in breakdown of the basement membrane. Our data reveal that the meninges regulate the development of the skull and cerebral cortex by controlling aspects of the formation of these neighboring structures. Furthermore, we provide evidence that defects in meningeal differentiation can lead to severe cortical dysplasia.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Fatores de Transcrição Forkhead/genética , Meninges/citologia , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Córtex Cerebral/patologia , Etilnitrosoureia , Meninges/patologia , Camundongos , Neurônios/patologia , Mutação Puntual
9.
Dev Biol ; 287(2): 378-89, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16229832

RESUMO

Sonic Hedgehog (Shh) signals are transduced into nuclear ratios of Gli transcriptional activator versus repressor. The initial part of this process is accomplished by Shh acting through Patched (Ptc) to regulate Smoothened (Smo) activity. The mechanisms by which Ptc regulates Smo, and Smo activity is transduced to processing of Gli proteins remain unclear. Recently, a forward genetic approach in mice identified a role for intraflagellar transport (IFT) genes in Shh signal transduction, downstream of Patched (Ptc) and Rab23. Here, we show that the retrograde motor for IFT is required in the mouse for the phenotypic expression of both Gli activator and repressor function and for effective proteolytic processing of Gli3. Furthermore, we show that the localization of Smo to primary cilia is disrupted in mutants. These data indicate that primary cilia act as specialized signal transduction organelles required for coupling Smo activity to the biochemical processing of Gli3 protein.


Assuntos
Cílios/metabolismo , Dineínas/metabolismo , Fatores de Transcrição Kruppel-Like/fisiologia , Proteínas Motores Moleculares/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Sequência de Aminoácidos , Animais , Padronização Corporal , Cílios/ultraestrutura , Dineínas/genética , Extremidades/embriologia , Flagelos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Microscopia Eletrônica de Varredura , Proteínas Motores Moleculares/genética , Dados de Sequência Molecular , Mutação , Proteínas do Tecido Nervoso/metabolismo , Prosencéfalo/anormalidades , Prosencéfalo/embriologia , Transporte Proteico/genética , Receptor Smoothened , Medula Espinal/anormalidades , Medula Espinal/embriologia , Transativadores/fisiologia , Proteína Gli3 com Dedos de Zinco
10.
Dev Biol ; 270(1): 31-46, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15136139

RESUMO

Morphogenesis of the developing vascular network requires coordinated regulation of an extensive array of endothelial cell behaviors. Precisely regulated signaling molecules such as vascular endothelial growth factor (VEGF) direct some of these endothelial behaviors. Newly forming blood vessels also become subjected to novel biomechanical forces upon initiation of cardiac contractions. We report here the identification of a recessive mouse mutation termed shrunken-head (shru) that disrupts function of the Titin gene. Titin was found to be required for the initiation of proper heart contractions as well as for maintaining the correct overall shape and orientation of individual cardiomyocytes. Cardiac dysfunction in shrunken-head mutant embryos provided an opportunity to study the effects of lack of blood circulation on the morphogenesis of endothelial cells. Without blood flow, differentiating endothelial cells display defects in their shapes and patterns of cell-cell contact. These endothelial cells, without exposure to blood circulation, have an abnormal distribution within vasculogenic vessels. Further effects of absent blood flow include abnormal spatial regulation of angiogenesis and elevated VEGF signaling. The shrunken-head mutation has provided an in vivo model to precisely define the roles of circulation on cellular and network aspects of vascular morphogenesis.


Assuntos
Endotélio Vascular/embriologia , Morfogênese/fisiologia , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutação , Neovascularização Fisiológica , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Animais , Circulação Sanguínea , Morte Celular , Tamanho Celular , Mapeamento Cromossômico , Conectina , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/anormalidades , Endotélio Vascular/citologia , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Contração Miocárdica/fisiologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fenótipo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Saco Vitelino/irrigação sanguínea
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