Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Dis Model Mech ; 15(2)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722956

RESUMO

22q11.2 Deletion Syndrome (22q11DS) is a neurodevelopmental disorder associated with cranial nerve anomalies and disordered oropharyngeal function, including pediatric dysphagia. Using the LgDel 22q11DS mouse model, we investigated whether sensory neuron differentiation in the trigeminal ganglion (CNgV), which is essential for normal orofacial function, is disrupted. We did not detect changes in cranial placode cell translocation or neural crest migration at early stages of LgDel CNgV development. However, as the ganglion coalesces, proportions of placode-derived LgDel CNgV cells increase relative to neural crest cells. In addition, local aggregation of placode-derived cells increases and aggregation of neural crest-derived cells decreases in LgDel CNgV. This change in cell-cell relationships was accompanied by altered proliferation of placode-derived cells at embryonic day (E)9.5, and premature neurogenesis from neural crest-derived precursors, reflected by an increased frequency of asymmetric neurogenic divisions for neural crest-derived precursors by E10.5. These early differences in LgDel CNgV genesis prefigure changes in sensory neuron differentiation and gene expression by postnatal day 8, when early signs of cranial nerve dysfunction associated with pediatric dysphagia are observed in LgDel mice. Apparently, 22q11 deletion destabilizes CNgV sensory neuron genesis and differentiation by increasing variability in cell-cell interaction, proliferation and sensory neuron differentiation. This early developmental divergence and its consequences may contribute to oropharyngeal dysfunction, including suckling, feeding and swallowing disruptions at birth, and additional orofacial sensory/motor deficits throughout life.

2.
Hum Mol Genet ; 29(18): 3081-3093, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-32901287

RESUMO

We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel+/- mouse embryos, a genomically accurate 22q11.2DS model, and 3D imaging to identify and quantify phenotypes that could not be resolved using existing methods. We assessed these phenotypes in three 22q11.2-related genotypes to determine whether individual CN V motor and sensory axons wander, branch and sprout aberrantly in register with altered anterior-posterior hindbrain patterning and gross morphological disruption of CN V seen in LgDel+/-. In the additional 22q11.2-related genotypes: Tbx1+/-, Ranbp1-/-, Ranbp1+/- and LgDel+/-:Raldh2+/-; axon phenotypes are seen when hindbrain patterning and CN V gross morphology is altered, but not when it is normal or restored toward WT. This disordered growth of CN V sensory and motor axons, whose appropriate targeting is critical for optimal S/F/S, may be an early, critical determinant of imprecise innervation leading to inefficient oropharyngeal function associated with 22q11.2 deletion from birth onward.

4.
Birth Defects Res ; 112(16): 1194-1208, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32431076

RESUMO

BACKGROUND: Vitamin A regulates patterning of the pharyngeal arches, cranial nerves, and hindbrain that are essential for feeding and swallowing. In the LgDel mouse model of 22q11.2 deletion syndrome (22q11DS), morphogenesis of multiple structures involved in feeding and swallowing are dysmorphic. We asked whether changes in maternal dietary Vitamin A intake can modify cranial nerve, hindbrain and pharyngeal arch artery development in the embryo as well as lung pathology that can be a sign of aspiration dysphagia in LgDel pups. METHODS: Three defined amounts of vitamin A (4, 10, and 16 IU/g) were provided in the maternal diet. Cranial nerve, hindbrain and pharyngeal arch artery development was evaluated in embryos and inflammation in the lungs of pups to determine the impact of altering maternal diet on these phenotypes. RESULTS: Reduced maternal vitamin A intake improved whereas increased intake exacerbated lung inflammation in LgDel pups. These changes were accompanied by increased incidence and/or severity of pharyngeal arch artery and cranial nerve V (CN V) abnormalities in LgDel embryos as well as altered expression of Cyp26b1 in the hindbrain. CONCLUSIONS: Our studies demonstrate that variations in maternal vitamin A intake can influence the incidence and severity of phenotypes in a mouse model 22q11.2 deletion syndrome.

5.
Hum Mol Genet ; 29(6): 1002-1017, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32047912

RESUMO

LgDel mice, which model the heterozygous deletion of genes at human chromosome 22q11.2 associated with DiGeorge/22q11.2 deletion syndrome (22q11DS), have cranial nerve and craniofacial dysfunction as well as disrupted suckling, feeding and swallowing, similar to key 22q11DS phenotypes. Divergent trigeminal nerve (CN V) differentiation and altered trigeminal ganglion (CNgV) cellular composition prefigure these disruptions in LgDel embryos. We therefore asked whether a distinct transcriptional state in a specific population of early differentiating LgDel cranial sensory neurons, those in CNgV, a major source of innervation for appropriate oropharyngeal function, underlies this departure from typical development. LgDel versus wild-type (WT) CNgV transcriptomes differ significantly at E10.5 just after the ganglion has coalesced. Some changes parallel altered proportions of cranial placode versus cranial neural crest-derived CNgV cells. Others are consistent with a shift in anterior-posterior patterning associated with divergent LgDel cranial nerve differentiation. The most robust quantitative distinction, however, is statistically verifiable increased variability of expression levels for most of the over 17 000 genes expressed in common in LgDel versus WT CNgV. Thus, quantitative expression changes of functionally relevant genes and increased stochastic variation across the entire CNgV transcriptome at the onset of CN V differentiation prefigure subsequent disruption of cranial nerve differentiation and oropharyngeal function in LgDel mice.

6.
Annu Rev Neurosci ; 43: 315-336, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32101484

RESUMO

All mammals must suckle and swallow at birth, and subsequently chew and swallow solid foods, for optimal growth and health. These initially innate behaviors depend critically upon coordinated development of the mouth, tongue, pharynx, and larynx as well as the cranial nerves that control these structures. Disrupted suckling, feeding, and swallowing from birth onward-perinatal dysphagia-is often associated with several neurodevelopmental disorders that subsequently alter complex behaviors. Apparently, a broad range of neurodevelopmental pathologic mechanisms also target oropharyngeal and cranial nerve differentiation. These aberrant mechanisms, including altered patterning, progenitor specification, and neurite growth, prefigure dysphagia and may then compromise circuits for additional behavioral capacities. Thus, perinatal dysphagia may be an early indicator of disrupted genetic and developmental programs that compromise neural circuits and yield a broad range of behavioral deficits in neurodevelopmental disorders.

7.
Neuron ; 102(6): 1127-1142.e3, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31079872

RESUMO

Under-connectivity between cerebral cortical association areas may underlie cognitive deficits in neurodevelopmental disorders, including the 22q11.2 deletion syndrome (22q11DS). Using the LgDel 22q11DS mouse model, we assessed cellular, molecular, and developmental origins of under-connectivity and its consequences for cognitive function. Diminished 22q11 gene dosage reduces long-distance projections, limits axon and dendrite growth, and disrupts mitochondrial and synaptic integrity in layer 2/3 but not 5/6 projection neurons (PNs). Diminished dosage of Txnrd2, a 22q11 gene essential for reactive oxygen species catabolism in brain mitochondria, recapitulates these deficits in WT layer 2/3 PNs; Txnrd2 re-expression in LgDel layer 2/3 PNs rescues them. Anti-oxidants reverse LgDel- or Txnrd2-related layer 2/3 mitochondrial, circuit, and cognitive deficits. Accordingly, Txnrd2-mediated oxidative stress reduces layer 2/3 connectivity and impairs cognition in the context of 22q11 deletion. Anti-oxidant restoration of mitochondrial integrity, cortical connectivity, and cognitive behavior defines oxidative stress as a therapeutic target in neurodevelopmental disorders.


Assuntos
Córtex Cerebral/metabolismo , Disfunção Cognitiva/genética , Síndrome de DiGeorge/genética , Mitocôndrias/metabolismo , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Redutase 2/genética , Animais , Axônios/ultraestrutura , Comportamento Animal , Córtex Cerebral/citologia , Dendritos/ultraestrutura , Modelos Animais de Doenças , Córtex Entorrinal/metabolismo , Lobo Frontal/metabolismo , Dosagem de Genes , Camundongos , Mitocôndrias/ultraestrutura , Vias Neurais , Neurônios/ultraestrutura , Sinapses/metabolismo , Sinapses/ultraestrutura
8.
Genesis ; 55(6)2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28316121

RESUMO

Many molecular factors required for later stages of neuronal differentiation have been identified; however, much less is known about the early events that regulate the initial establishment of the neuroectoderm. We have used an in vitro embryonic stem cell (ESC) differentiation model to investigate early events of neuronal differentiation and to define the role of mouse Foxd4, an ortholog of a forkhead-family transcription factor central to Xenopus neural plate/neuroectodermal precursor development. We found that Foxd4 is a necessary regulator of the transition from pluripotent ESC to neuroectodermal stem cell, and its expression is necessary for neuronal differentiation. Mouse Foxd4 expression is not only limited to the neural plate but it is also expressed and apparently functions to regulate neurogenesis in the olfactory placode. These in vitro results suggest that mouse Foxd4 has a similar function to its Xenopus ortholog; this was confirmed by successfully substituting murine Foxd4 for its amphibian counterpart in overexpression experiments. Thus, Foxd4 appears to regulate the initial steps in establishing neuroectodermal precursors during initial development of the nervous system.


Assuntos
Células-Tronco Embrionárias/metabolismo , Fatores de Transcrição Forkhead/genética , Células-Tronco Neurais/metabolismo , Neurogênese , Animais , Células Cultivadas , Células-Tronco Embrionárias/citologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Placa Neural/citologia , Placa Neural/metabolismo , Células-Tronco Neurais/citologia , Xenopus
9.
Neuron ; 93(3): 476-479, 2017 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-28182903

RESUMO

The ever-expanding number of genes that are mutated in autism is showing us how imbalances in fundamental cellular processes can lead to disease. A recent study by Tarlungeanu et al. (2016) identifies a form of ASD resulting from a failure of the brain to properly import amino acids.


Assuntos
Transtorno Autístico , Encéfalo , Aminoácidos
10.
Genetics ; 203(2): 905-22, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27075724

RESUMO

Genes encoding nuclear receptors (NRs) are attractive as candidates for investigating the evolution of gene regulation because they (1) have a direct effect on gene expression and (2) modulate many cellular processes that underlie development. We employed a three-phase investigation linking NR molecular evolution among primates with direct experimental assessment of NR function. Phase 1 was an analysis of NR domain evolution and the results were used to guide the design of phase 2, a codon-model-based survey for alterations of natural selection within the hominids. By using a series of reliability and robustness analyses we selected a single gene, NR2C1, as the best candidate for experimental assessment. We carried out assays to determine whether changes between the ancestral and extant NR2C1s could have impacted stem cell pluripotency (phase 3). We evaluated human, chimpanzee, and ancestral NR2C1 for transcriptional modulation of Oct4 and Nanog (key regulators of pluripotency and cell lineage commitment), promoter activity for Pepck (a proxy for differentiation in numerous cell types), and average size of embryological stem cell colonies (a proxy for the self-renewal capacity of pluripotent cells). Results supported the signal for alteration of natural selection identified in phase 2. We suggest that adaptive evolution of gene regulation has impacted several aspects of pluripotentiality within primates. Our study illustrates that the combination of targeted evolutionary surveys and experimental analysis is an effective strategy for investigating the evolution of gene regulation with respect to developmental phenotypes.


Assuntos
Diferenciação Celular/genética , Evolução Molecular , Hominidae/genética , Membro 1 do Grupo C da Subfamília 2 de Receptores Nucleares/genética , Células-Tronco Pluripotentes/citologia , Animais , Linhagem Celular , Sequência Conservada , Humanos , Camundongos , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Membro 1 do Grupo C da Subfamília 2 de Receptores Nucleares/química , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Células-Tronco Pluripotentes/metabolismo , Domínios Proteicos
11.
Genesis ; 54(6): 334-49, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27092474

RESUMO

The decision by embryonic ectoderm to give rise to epidermal versus neural derivatives is the result of signaling events during blastula and gastrula stages. However, there also is evidence in Xenopus that cleavage stage blastomeres contain maternally derived molecules that bias them toward a neural fate. We used a blastomere explant culture assay to test whether maternally deposited transcription factors bias 16-cell blastomere precursors of epidermal or neural ectoderm to express early zygotic neural genes in the absence of gastrulation interactions or exogenously supplied signaling factors. We found that Foxd4l1, Zic2, Gmnn, and Sox11 each induced explants made from ventral, epidermis-producing blastomeres to express early neural genes, and that at least some of the Foxd4l1 and Zic2 activities are required at cleavage stages. Similarly, providing extra Foxd4l1 or Zic2 to explants made from dorsal, neural plate-producing blastomeres significantly increased the expression of early neural genes, whereas knocking down either significantly reduced them. These results show that maternally delivered transcription factors bias cleavage stage blastomeres to a neural fate. We demonstrate that mouse and human homologs of Foxd4l1 have similar functional domains compared to the frog protein, as well as conserved transcriptional activities when expressed in Xenopus embryos and blastomere explants. genesis 54:334-349, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Diferenciação Celular/genética , Ectoderma/crescimento & desenvolvimento , Fatores de Transcrição Forkhead/genética , Placa Neural/crescimento & desenvolvimento , Animais , Blastômeros/metabolismo , Blástula/crescimento & desenvolvimento , Ectoderma/metabolismo , Fatores de Transcrição Forkhead/biossíntese , Gástrula/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Placa Neural/metabolismo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Proteínas de Xenopus/biossíntese , Proteínas de Xenopus/genética , Xenopus laevis/genética , Xenopus laevis/crescimento & desenvolvimento , Zigoto/crescimento & desenvolvimento
12.
Front Mol Neurosci ; 9: 20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27047334

RESUMO

Long-term opioid treatment results in reduced therapeutic efficacy and in turn leads to an increase in the dose required to produce equivalent pain relief and alleviate break-through or insurmountable pain. Altered gene expression is a likely means for inducing long-term neuroadaptations responsible for tolerance. Studies conducted by our laboratory (Tapocik et al., 2009) revealed a network of gene expression changes occurring in canonical pathways involved in neuroplasticity, and uncovered miRNA processing as a potential mechanism. In particular, the mRNA coding the protein responsible for processing miRNAs, Dicer1, was positively correlated with the development of analgesic tolerance. The purpose of the present study was to test the hypothesis that miRNAs play a significant role in the development of analgesic tolerance as measured by thermal nociception. Dicer1 knockdown, miRNA profiling, bioinformatics, and confirmation of high value targets were used to test the proposition. Regionally targeted Dicer1 knockdown (via shRNA) had the anticipated consequence of eliminating the development of tolerance in C57BL/6J (B6) mice, thus supporting the involvement of miRNAs in the development of tolerance. MiRNA expression profiling identified a core set of chronic morphine-regulated miRNAs (miR's 27a, 9, 483, 505, 146b, 202). Bioinformatics approaches were implemented to identify and prioritize their predicted target mRNAs. We focused our attention on miR27a and its predicted target serpin peptidase inhibitor clade I (Serpini1) mRNA, a transcript known to be intricately involved in dendritic spine density regulation in a manner consistent with chronic morphine's consequences and previously found to be correlated with the development of analgesic tolerance. In vitro reporter assay confirmed the targeting of the Serpini1 3'-untranslated region by miR27a. Interestingly miR27a was found to positively regulate Serpini1 mRNA and protein levels in multiple neuronal cell lines. Lastly, Serpini1 knockout mice developed analgesic tolerance at a slower rate than wild-type mice thus confirming a role for the protein in analgesic tolerance. Overall, these results provide evidence to support a specific role for miR27a and Serpini1 in the behavioral response to chronic opioid administration (COA) and suggest that miRNA expression and mRNA targeting may underlie the neuroadaptations that mediate tolerance to the analgesic effects of morphine.

13.
Dev Biol ; 415(2): 228-241, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-26988119

RESUMO

We compared apparent origins, cellular diversity and regulation of initial axon growth for differentiating cranial sensory neurons. We assessed the molecular and cellular composition of the developing olfactory and otic placodes, and cranial sensory ganglia to evaluate contributions of ectodermal placode versus neural crest at each site. Special sensory neuron populations-the olfactory and otic placodes, as well as those in vestibulo-acoustic ganglion- are entirely populated with cells expressing cranial placode-associated, rather than neural crest-associated markers. The remaining cranial sensory ganglia are a mosaic of cells that express placode-associated as well as neural crest-associated markers. We found two distinct populations of neural crest in the cranial ganglia: the first, as expected, is labeled by Wnt1:Cre mediated recombination. The second is not labeled by Wnt1:Cre recombination, and expresses both Sox10 and FoxD3. These populations-Wnt1:Cre recombined, and Sox10/Foxd3-expressing- are proliferatively distinct from one another. Together, the two neural crest-associated populations are substantially more proliferative than their placode-associated counterparts. Nevertheless, the apparently placode- and neural crest-associated populations are similarly sensitive to altered signaling that compromises cranial morphogenesis and differentiation. Acute disruption of either Fibroblast growth factor (Fgf) or Retinoic acid (RA) signaling alters axon growth and cell death, but does not preferentially target any of the three distinct populations. Apparently, mosaic derivation and diversity of precursors and early differentiating neurons, modulated uniformly by local signals, supports early cranial sensory neuron differentiation and growth.


Assuntos
Nervos Cranianos/citologia , Células Receptoras Sensoriais/citologia , Animais , Apoptose , Axônios/fisiologia , Diferenciação Celular , Linhagem da Célula , Nervos Cranianos/embriologia , Ectoderma/citologia , Fatores de Crescimento de Fibroblastos/fisiologia , Gânglios Sensitivos/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas Luminescentes/análise , Proteínas Luminescentes/genética , Camundongos , Camundongos Endogâmicos C57BL , Crista Neural/citologia , Neurogênese , Fatores de Transcrição/genética , Tretinoína/fisiologia , Proteína Wnt1/fisiologia
14.
Gene Expr Patterns ; 20(1): 71-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26712358

RESUMO

Comparative genomic analysis of the nuclear receptor family suggests that the testicular receptor 2, Nr2c1, undergoes positive selection in the human-chimpanzee clade based upon a significant increase in nonsynonymous compared to synonymous substitutions. Previous in situ analyses of Nr2c1 lacked the temporal range and spatial resolution necessary to characterize cellular expression of this gene from early to mid gestation, when many nuclear receptors are key regulators of tissue specific stem or progenitor cells. Thus, we asked whether Nr2c1 protein is associated with stem cell populations in the mid-gestation mouse embryo. Nr2c1 is robustly expressed in the developing olfactory epithelium. Its expression in the olfactory epithelium shifts from multiple progenitor classes at early stages to primarily transit amplifying cells later in olfactory epithelium development. In the early developing central nervous system, Nr2c1 is limited to the anterior telencephalon/olfactory bulb anlagen, coincident with Nestin-positive neuroepithelial stem cells. Nr2c1 is also seen in additional cranial sensory specializations including cells surrounding the mystacial vibrissae, the retinal pigment epithelium and Scarpa's ganglion. Nr2c1 was also detected in a subset of mesenchymal cells in developing teeth and cranial bones. The timing and distribution of embryonic expression suggests that Nr2c1 is primarily associated with the early genesis of mammalian cranial sensory neurons and craniofacial skeletal structures. Thus, Nr2c1 may be a candidate for mediating parallel adaptive changes in cranial neural sensory specializations such as the olfactory epithelium, retina and mystacial vibrissae and in non-neural craniofacial features including teeth.


Assuntos
Membro 1 do Grupo C da Subfamília 2 de Receptores Nucleares/biossíntese , Mucosa Olfatória/embriologia , Crânio/embriologia , Células-Tronco/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Ossos Faciais/embriologia , Ossos Faciais/metabolismo , Gânglios Sensitivos/embriologia , Gânglios Sensitivos/metabolismo , Perfilação da Expressão Gênica , Camundongos , Células-Tronco Neurais/metabolismo , Bulbo Olfatório/metabolismo , Mucosa Olfatória/citologia , Mucosa Olfatória/metabolismo , Crânio/citologia , Crânio/metabolismo , Telencéfalo/metabolismo , Dente/embriologia , Dente/metabolismo
15.
Dev Biol ; 409(2): 329-42, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26554723

RESUMO

Pediatric dysphagia-feeding and swallowing difficulties that begin at birth, last throughout childhood, and continue into maturity--is one of the most common, least understood complications in children with developmental disorders. We argue that a major cause of pediatric dysphagia is altered hindbrain patterning during pre-natal development. Such changes can compromise craniofacial structures including oropharyngeal muscles and skeletal elements as well as motor and sensory circuits necessary for normal feeding and swallowing. Animal models of developmental disorders that include pediatric dysphagia in their phenotypic spectrum can provide mechanistic insight into pathogenesis of feeding and swallowing difficulties. A fairly common human genetic developmental disorder, DiGeorge/22q11.2 Deletion Syndrome (22q11DS) includes a substantial incidence of pediatric dysphagia in its phenotypic spectrum. Infant mice carrying a parallel deletion to 22q11DS patients have feeding and swallowing difficulties that approximate those seen in pediatric dysphagia. Altered hindbrain patterning, craniofacial malformations, and changes in cranial nerve growth prefigure these difficulties. Thus, in addition to craniofacial and pharyngeal anomalies that arise independently of altered neural development, pediatric dysphagia may result from disrupted hindbrain patterning and its impact on peripheral and central neural circuit development critical for feeding and swallowing. The mechanisms that disrupt hindbrain patterning and circuitry may provide a foundation to develop novel therapeutic approaches for improved clinical management of pediatric dysphagia.


Assuntos
Transtornos de Deglutição/patologia , Crescimento e Desenvolvimento , Animais , Criança , Modelos Animais de Doenças , Humanos , Modelos Biológicos , Rede Nervosa/fisiopatologia
16.
Prog Neurobiol ; 130: 1-28, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25866365

RESUMO

Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic "model" syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that "modeling a model", in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development.


Assuntos
Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Predisposição Genética para Doença/genética , Camundongos , Animais , Córtex Cerebral/patologia , Modelos Animais de Doenças , Humanos , Esquizofrenia/genética
17.
Cereb Cortex ; 25(10): 3977-93, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25452572

RESUMO

Ranbp1, a Ran GTPase-binding protein implicated in nuclear/cytoplasmic trafficking, is included within the DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS) critical region associated with behavioral impairments including autism and schizophrenia. Ranbp1 is highly expressed in the developing forebrain ventricular/subventricular zone but has no known obligate function during brain development. We assessed the role of Ranbp1 in a targeted mouse mutant. Ranbp1(-/-) mice are not recovered live at birth, and over 60% of Ranbp1(-/-) embryos are exencephalic. Non-exencephalic Ranbp1(-/-) embryos are microcephalic, and proliferation of cortical progenitors is altered. At E10.5, radial progenitors divide more slowly in the Ranpb1(-/-) dorsal pallium. At E14.5, basal, but not apical/radial glial progenitors, are compromised in the cortex. In both E10.5 apical and E14.5 basal progenitors, M phase of the cell cycle appears selectively retarded by loss of Ranpb1 function. Ranbp1(-/-)-dependent proliferative deficits substantially diminish the frequency of layer 2/3, but not layer 5/6 cortical projection neurons. Ranbp1(-/-) cortical phenotypes parallel less severe alterations in LgDel mice that carry a deletion parallel to many (but not all) 22q11.2 DS patients. Thus, Ranbp1 emerges as a microcephaly gene within the 22q11.2 deleted region that may contribute to altered cortical precursor proliferation and neurogenesis associated with broader 22q11.2 deletion.


Assuntos
Córtex Cerebral/embriologia , Síndrome de DiGeorge/embriologia , Síndrome de DiGeorge/genética , Microcefalia/genética , Células-Tronco Neurais/fisiologia , Neurogênese/genética , Proteínas Nucleares/fisiologia , Animais , Polaridade Celular , Proliferação de Células/genética , Córtex Cerebral/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Ventrículos Laterais/embriologia , Ventrículos Laterais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Neuroepiteliais/fisiologia , Proteínas Nucleares/genética
18.
Dis Model Mech ; 7(2): 245-57, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24357327

RESUMO

We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS), a common developmental disorder that frequently includes perinatal dysphagia--debilitating feeding, swallowing and nutrition difficulties from birth onward--within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA) signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V), glossopharyngeal (IX) or vagus (X) cranial nerves (CNs) that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.


Assuntos
Deleção Cromossômica , Nervos Cranianos/embriologia , Nervos Cranianos/patologia , Transtornos de Deglutição/embriologia , Transtornos de Deglutição/patologia , Animais , Animais Recém-Nascidos , Padronização Corporal/genética , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/fisiopatologia , Deglutição , Transtornos de Deglutição/genética , Transtornos de Deglutição/fisiopatologia , Síndrome de DiGeorge , Modelos Animais de Doenças , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/patologia , Comportamento Alimentar , Feminino , Dosagem de Genes , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos , Fenótipo , Rombencéfalo/anormalidades , Rombencéfalo/embriologia , Rombencéfalo/patologia , Transdução de Sinais , Proteínas com Domínio T/metabolismo , Tretinoína/metabolismo
19.
Am J Stem Cells ; 2(2): 74-94, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23862097

RESUMO

THE EARLIEST STEPS OF EMBRYONIC NEURAL DEVELOPMENT ARE ORCHESTRATED BY SETS OF TRANSCRIPTION FACTORS THAT CONTROL AT LEAST THREE PROCESSES: the maintenance of proliferative, pluripotent precursors that expand the neural ectoderm; their transition to neurally committed stem cells comprising the neural plate; and the onset of differentiation of neural progenitors. The transition from one step to the next requires the sequential activation of each gene set and then its down-regulation at the correct developmental times. Herein, we review how these gene sets interact in a transcriptional network to regulate these early steps in neural development. A key gene in this regulatory network is FoxD4L1, a member of the forkhead box (Fox) family of transcription factors. Knock-down experiments in Xenopus embryos show that FoxD4L1 is required for the expression of the other neural transcription factors, whereas increased FoxD4L1 levels have three different effects on these genes: up-regulation of neural ectoderm precursor genes; transient down-regulation of neural plate stem cell genes; and down-regulation of neural progenitor differentiation genes. These different effects indicate that FoxD4L1 maintains neural ectodermal precursors in an immature, proliferative state, and counteracts premature neural stem cell and neural progenitor differentiation. Because it both up-regulates and down-regulates genes, we characterized the regions of the FoxD4L1 protein that are specifically involved in these transcriptional functions. We identified a transcriptional activation domain in the N-terminus and at least two domains in the C-terminus that are required for transcriptional repression. These functional domains are highly conserved in the mouse and human homologues. Preliminary studies of the related FoxD4 gene in cultured mouse embryonic stem cells indicate that it has a similar role in promoting immature neural ectodermal precursors and delaying neural progenitor differentiation. These studies in Xenopus embryos and mouse embryonic stem cells indicate that FoxD4L1/FoxD4 has the important function of regulating the balance between the genes that expand neural ectodermal precursors and those that promote neural stem/progenitor differentiation. Thus, regulating the level of expression of FoxD4 may be important in stem cell protocols designed to create immature neural cells for therapeutic uses.

20.
Hum Mol Genet ; 22(2): 300-12, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23077214

RESUMO

We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1 deletion syndrome (22q11DS). Sonic hedgehog (Shh) and retinoic acid (RA) signaling is altered in the brain and heart-clinically significant 22q11DS phenotypic sites-in LgDel mouse embryos, an established 22q11DS model. LgDel embryos treated with cyclopamine, an Shh inhibitor, or carrying mutations in Gli3(Xtj), an Shh-signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequencies in control or single-mutant embryos. Similarly, RA exposure or genetic loss of RA function via heterozygous mutation of the RA synthetic enzyme Raldh2 induces novel cranial anomalies and enhances cardiovascular phenotypes in LgDel but not other genotypes. These changes are not seen in heterozygous Tbx1 mutant embryos-a 22q11 gene thought to explain much of 22q11DS pathogenesis-in which Shh or RA signaling has been similarly modified. Our results suggest that full dosage of 22q11 genes beyond Tbx1 establish an adaptive range for morphogenetic signaling via Shh and RA. When this adaptive range is constricted by diminished dosage of 22q11 genes, embryos are sensitized to otherwise benign changes in Shh and RA signaling. Such sensitization, in the face of environmental or genetic factors that modify Shh or RA signaling, may explain variability in 22q11DS morphogenetic phenotypes.


Assuntos
Adaptação Biológica , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/metabolismo , Dosagem de Genes , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Tretinoína/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Camundongos Knockout , Morfogênese/genética , Tubo Neural/embriologia , Tubo Neural/metabolismo , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...