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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.
eNeuro ; 7(5)2020.
Artigo em Inglês | MEDLINE | ID: mdl-32855199

RESUMO

We asked whether the physiological and morphologic properties of hypoglossal motor neurons (CNXII MNs) that innervate protruder or retractor tongue muscles are disrupted in neonatal LgDel mice that carry a heterozygous deletion parallel to that associated with DiGeorge/22q11.2 deletion syndrome (22q11.2DS). Disrupted coordination of tongue movement in LgDel mouse pups may contribute to suckling, feeding, and swallowing (S/F/S) disruptions that parallel pediatric dysphagia in infants and toddlers with 22q11.2DS. Using an in vitro rhythmically active medullary slice preparation, we found spontaneous firing as well as IPSC frequency differed significantly in neonatal LgDel versus wild-type (WT) protruder and retractor CNXII MNs that were identified by retrograde tracing from their target muscles. In response to respiration-related activity, initiation and decay of transiently increased firing in WT protruder MNs is delayed in LgDel, accompanied by altered excitatory/inhibitory (E/I) balance. In addition, LgDel retractor MNs have a transient increase in firing with diminished IPSC frequency that is not seen in WT. There were no significant differences in cell body volume of either XII class in WT and LgDel Sholl analysis showed the total numbers of dendritic intersections (at 50- and 90-µm radii from the cell soma) were significantly greater for LgDel versus WT retractor MNs. Thus, the physiological, synaptic and cellular properties of distinct classes of CNXII MNs that coordinate tongue movement in neonatal WT mice are altered in LgDel Such changes could contribute to sub-optimal coordination of S/F/S that underlies pediatric dysphagia in 22q11.2DS.

3.
Front Neurol ; 11: 4, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082240

RESUMO

Disrupted development of oropharyngeal structures as well as cranial nerve and brainstem circuits may lead to feeding and swallowing difficulties in children with 22q11. 2 deletion syndrome (22q11DS). We previously demonstrated aspiration-based dysphagia during early postnatal life in the LgDel mouse model of 22q11DS along with disrupted oropharyngeal morphogenesis and divergent differentiation and function of cranial motor and sensory nerves. We now ask whether feeding and swallowing deficits persist in adult LgDel mice using methods analogous to those used in human patients to evaluate feeding and swallowing dysfunction. Compared to wild-type mice, videofluoroscopic swallow study revealed that LgDel mice have altered feeding and swallowing behaviors, including slower lick rates, longer inter-lick intervals, and longer pharyngeal transit times with liquid consistency. Transoral endoscopic assessment identified minor structural anomalies of the palate and larynx in one-third of the LgDel mice examined. Video surveillance of feeding-related behaviors showed that LgDel mice eat and drink more frequently. Furthermore, LgDel animals engage in another oromotor behavior, grooming, more frequently, implying that divergent craniofacial and cranial nerve structure and function result in altered oromotor coordination. Finally, LgDel mice have significantly increased lung inflammation, a potential sign of aspiration-based dysphagia, consistent with results from our previous studies of early postnatal animals showing aspiration-related lung inflammation. Thus, oromotor dysfunction, feeding, and swallowing difficulties and their consequences persist in the LgDel 22q11DS mouse model. Apparently, postnatal growth and/or neural plasticity does not fully resolve deficits due to anomalous hindbrain, craniofacial, and cranial nerve development that prefigure perinatal dysphagia in 22q11DS. This new recognition of persistent challenges with feeding and swallowing may provide opportunities for improved therapeutic intervention for adolescents and adults with 22q11DS, as well as others with a history of perinatal feeding and swallowing disorders.

4.
J Neurodev Disord ; 11(1): 7, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174463

RESUMO

BACKGROUND: 22q11.2 deletion syndrome (22q11DS), a copy number variation (CNV) disorder, occurs in approximately 1:4000 live births due to a heterozygous microdeletion at position 11.2 (proximal) on the q arm of human chromosome 22 (hChr22) (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011). This disorder was known as DiGeorge syndrome, Velo-cardio-facial syndrome (VCFS) or conotruncal anomaly face syndrome (CTAF) based upon diagnostic cardiovascular, pharyngeal, and craniofacial anomalies (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011; Burn et al., J Med Genet 30:822-4, 1993) before this phenotypic spectrum was associated with 22q11.2 CNVs. Subsequently, 22q11.2 deletion emerged as a major genomic lesion associated with vulnerability for several clinically defined behavioral deficits common to a number of neurodevelopmental disorders (Fernandez et al., Principles of Developmental Genetics, 2015; Robin and Shprintzen, J Pediatr 147:90-6, 2005; Schneider et al., Am J Psychiatry 171:627-39, 2014). RESULTS: The mechanistic relationships between heterozygously deleted 22q11.2 genes and 22q11DS phenotypes are still unknown. We assembled a comprehensive "line-up" of the 36 protein coding loci in the 1.5 Mb minimal critical deleted region on hChr22q11.2, plus 20 protein coding loci in the distal 1.5 Mb that defines the 3 Mb typical 22q11DS deletion. We categorized candidates based upon apparent primary cell biological functions. We analyzed 41 of these genes that encode known proteins to determine whether haploinsufficiency of any single 22q11.2 gene-a one gene to one phenotype correspondence due to heterozygous deletion restricted to that locus-versus complex multigenic interactions can account for single or multiple 22q11DS phenotypes. CONCLUSIONS: Our 22q11.2 functional genomic assessment does not support current theories of single gene haploinsufficiency for one or all 22q11DS phenotypes. Shared molecular functions, convergence on fundamental cell biological processes, and related consequences of individual 22q11.2 genes point to a matrix of multigenic interactions due to diminished 22q11.2 gene dosage. These interactions target fundamental cellular mechanisms essential for development, maturation, or homeostasis at subsets of 22q11DS phenotypic sites.


Assuntos
Síndrome de DiGeorge/genética , Deleção de Genes , Genômica , Animais , Humanos
5.
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
6.
Eur J Neurosci ; 49(7): 888-899, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29883004

RESUMO

The organization and function of sensory systems, especially the mammalian visual system, has been the focus of philosophers and scientists for centuries-from Descartes and Newton onward. Nevertheless, the utility of understanding development and its genetic foundations for deeper insight into neural function has been debated: Do you need to know how something is assembled-a car, for example-to understand how it works or how to use it-to turn on the ignition and drive? This review addresses this issue for sensory pathways. The pioneering work of the late Rainer W. (Ray) Guillery provides an unequivocal answer to this central question: Using genetics for mechanistic exploration of sensory system development yields essential knowledge of organization and function. Ray truly built the foundation for this now accepted tenet of modern neuroscience. His work on the development and reorganization of visual pathways in albino mammals-all with primary genetic mutations in genes for pigmentation-defined the genetic approach to neural systems development, function and plasticity. The work that followed his lead in a variety of sensory systems, including my own work in the developing olfactory system, proceeds directly from Ray's fundamental contributions.


Assuntos
Encéfalo/fisiologia , Genética Comportamental/história , Neurogênese , Neurociências/história , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , História do Século XX , História do Século XXI , Humanos
7.
Neuroscience ; 359: 1-7, 2017 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-28687307

RESUMO

DiGeorge/22q11.2 Deletion Syndrome (22q11DS) is a common genetic microdeletion syndrome that underlies several neurodevelopmental disorders including autism, attention deficit/hyperactivity disorder, and schizophrenia. In addition to cognitive impairments, those with 22q11DS have disrupted feeding and swallowing from birth onward. This perinatal dysphagia significantly compromises nutritional status, impairs appropriate weight gain, and can lead to life threatening aspiration-based infections. Appropriately timed excitation and inhibition of brainstem hypoglossal motor neurons, which innervate tongue muscles, is essential for proper feeding and swallowing. In this study we have examined changes in hypoglossal motor neuron function in the LgDel mouse model of 22q11DS. Hypoglossal motor neurons from LgDel mouse pups have action potentials with afterhyperpolarizations, mediated by a large conductance charybdotoxin-sensitive Ca-activated K current, that are significantly shorter in duration and greater in magnitude than those in wild-type pups. In addition, the amplitude, but not frequency, of glutamatergic excitatory glutamatergic postsynaptic currents (EPSCs) is diminished, and GABAergic, but not glycinergic, neurotransmission to hypoglossal motor neurons was reduced in LgDel animals. These observations provide a foundation for understanding the neurological changes in hypoglossal motor neuron function and their contribution to swallowing abnormalities that occur in DiGeorge/22q11.2 Deletion Syndrome.


Assuntos
Síndrome de DiGeorge/fisiopatologia , Nervo Hipoglosso/fisiopatologia , Bulbo/fisiopatologia , Potenciais da Membrana , Neurônios Motores/fisiologia , Animais , Feminino , Masculino , Camundongos Endogâmicos C57BL , Potenciais Sinápticos
8.
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
9.
Curr Top Dev Biol ; 111: 301-50, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25662264

RESUMO

Cranial sensory placodes derive from discrete patches of the head ectoderm and give rise to numerous sensory structures. During gastrulation, a specialized "neural border zone" forms around the neural plate in response to interactions between the neural and nonneural ectoderm and signals from adjacent mesodermal and/or endodermal tissues. This zone subsequently gives rise to two distinct precursor populations of the peripheral nervous system: the neural crest and the preplacodal ectoderm (PPE). The PPE is a common field from which all cranial sensory placodes arise (adenohypophyseal, olfactory, lens, trigeminal, epibranchial, otic). Members of the Six family of transcription factors are major regulators of PPE specification, in partnership with cofactor proteins such as Eya. Six gene activity also maintains tissue boundaries between the PPE, neural crest, and epidermis by repressing genes that specify the fates of those adjacent ectodermally derived domains. As the embryo acquires anterior-posterior identity, the PPE becomes transcriptionally regionalized, and it subsequently becomes subdivided into specific placodes with distinct developmental fates in response to signaling from adjacent tissues. Each placode is characterized by a unique transcriptional program that leads to the differentiation of highly specialized cells, such as neurosecretory cells, sensory receptor cells, chemosensory neurons, peripheral glia, and supporting cells. In this review, we summarize the transcriptional and signaling factors that regulate key steps of placode development, influence subsequent sensory neuron specification, and discuss what is known about mutations in some of the essential PPE genes that underlie human congenital syndromes.


Assuntos
Vias Aferentes/embriologia , Ectoderma/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Cabeça/embriologia , Modelos Biológicos , Placa Neural/embriologia , Transdução de Sinais/fisiologia , Ectoderma/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Placa Neural/metabolismo , Transdução de Sinais/genética
10.
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
11.
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.

12.
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
13.
Proc Natl Acad Sci U S A ; 109(45): 18601-6, 2012 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-23091025

RESUMO

Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, including schizophrenia and autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.2 gene dosage-the primary genetic lesion in 22q11.2 deletion syndrome (22q11.2 DS)-specifically compromises the distribution of early-generated parvalbumin-expressing interneurons in the Large Deletion (LgDel) 22q11.2DS mouse model. This change reflects cell-autonomous disruption of interneuron migration caused by altered expression of the cytokine C-X-C chemokine receptor type 4 (Cxcr4), an established regulator of this process. Cxcr4 is specifically reduced in LgDel migrating interneurons, and genetic analysis confirms that diminished Cxcr4 alters interneuron migration in LgDel mice. Thus, diminished 22q11.2 gene dosage disrupts cortical circuit development by modifying a critical molecular signaling pathway via Cxcr4 that regulates cortical interneuron migration and placement.


Assuntos
Movimento Celular/genética , Síndrome de DiGeorge/metabolismo , Síndrome de DiGeorge/patologia , Interneurônios/metabolismo , Interneurônios/patologia , Receptores CXCR4/metabolismo , Animais , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Heterozigoto , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Parvalbuminas/metabolismo
14.
Development ; 137(15): 2471-81, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20573694

RESUMO

Neural precursors in the developing olfactory epithelium (OE) give rise to three major neuronal classes - olfactory receptor (ORNs), vomeronasal (VRNs) and gonadotropin releasing hormone (GnRH) neurons. Nevertheless, the molecular and proliferative identities of these precursors are largely unknown. We characterized two precursor classes in the olfactory epithelium (OE) shortly after it becomes a distinct tissue at midgestation in the mouse: slowly dividing self-renewing precursors that express Meis1/2 at high levels, and rapidly dividing neurogenic precursors that express high levels of Sox2 and Ascl1. Precursors expressing high levels of Meis genes primarily reside in the lateral OE, whereas precursors expressing high levels of Sox2 and Ascl1 primarily reside in the medial OE. Fgf8 maintains these expression signatures and proliferative identities. Using electroporation in the wild-type embryonic OE in vitro as well as Fgf8, Sox2 and Ascl1 mutant mice in vivo, we found that Sox2 dose and Meis1 - independent of Pbx co-factors - regulate Ascl1 expression and the transition from lateral to medial precursor state. Thus, we have identified proliferative characteristics and a dose-dependent transcriptional network that define distinct OE precursors: medial precursors that are most probably transit amplifying neurogenic progenitors for ORNs, VRNs and GnRH neurons, and lateral precursors that include multi-potent self-renewing OE neural stem cells.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Neurônios/metabolismo , Mucosa Olfatória/metabolismo , Transcrição Genética , Animais , Ciclo Celular , Proliferação de Células , Eletroporação , Feminino , Imuno-Histoquímica/métodos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Mucosa Olfatória/embriologia , Células-Tronco/citologia
15.
Ann Neurol ; 67(4): 516-25, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20437587

RESUMO

OBJECTIVE: We sought to explore the genetic and molecular causes of Troyer syndrome, one of several complicated hereditary spastic paraplegias (HSPs). Troyer syndrome had been thought to be restricted to the Amish; however, we identified 2 Omani families with HSP, short stature, dysarthria and developmental delay-core features of Troyer syndrome-and a novel mutation in the SPG20 gene, which is also mutated in the Amish. In addition, we analyzed SPG20 expression throughout development to infer how disruption of this gene might generate the constellation of developmental and degenerative Troyer syndrome phenotypes. METHODS: Clinical characterization of 2 non-Amish families with Troyer syndrome was followed by linkage and sequencing analysis. Quantitative polymerase chain reaction and in situ hybridization analysis of SPG20 expression were carried out in embryonic and adult human and mouse tissue. RESULTS: Two Omani families carrying a novel SPG20 mutation displayed clinical features remarkably similar to the Amish patients with Troyer syndrome. SPG20 mRNA is expressed broadly but at low relative levels in the adult brain; however, it is robustly and specifically expressed in the limbs, face, and brain during early morphogenesis. INTERPRETATION: Null mutations in SPG20 cause Troyer syndrome, a specific clinical entity with developmental and degenerative features. Maximal expression of SPG20 in the limb buds and forebrain during embryogenesis may explain the developmental origin of the skeletal and cognitive defects observed in this disorder.


Assuntos
Predisposição Genética para Doença/genética , Doenças Neurodegenerativas/etiologia , Paraplegia/complicações , Paraplegia/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Adolescente , Adulto , Proteínas de Ciclo Celular , Pré-Escolar , Mapeamento Cromossômico , Análise Mutacional de DNA/métodos , Saúde da Família , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Omã , Paraplegia/patologia , Proteínas/metabolismo , RNA Mensageiro/genética , Adulto Jovem
16.
Proc Natl Acad Sci U S A ; 106(38): 16434-45, 2009 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-19805316

RESUMO

The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for "diseases of cortical connectivity" thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbumin-labeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism.


Assuntos
Córtex Cerebral/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 21/genética , Cromossomos de Mamíferos/genética , Síndrome de DiGeorge/genética , Animais , Proteínas de Ciclo Celular/genética , Diferenciação Celular , Proliferação de Células , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Ciclina D1/genética , Síndrome de DiGeorge/embriologia , Síndrome de DiGeorge/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Histonas/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfoproteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sintenia , Proteínas com Domínio T/genética
17.
J Neurosci ; 28(38): 9504-18, 2008 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-18799682

RESUMO

We characterized intrinsic and extrinsic specification of progenitors in the lateral and medial ganglionic eminences (LGE and MGE). We identified seven genes whose expression is enriched or restricted in either the LGE [biregional cell adhesion molecule-related/downregulated by oncogenes binding protein (Boc), Frizzled homolog 8 (Fzd8), Ankrd43 (ankyrin repeat domain-containing protein 43), and Ikzf1 (Ikaros family zinc finger 1)] or MGE [Map3k12 binding inhibitory protein 1 (Mbip); zinc-finger, SWIM domain containing 5 (Zswim5); and Adamts5 [a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5]]. Boc, Fzd8, Mbip, and Zswim5 are apparently expressed in LGE or MGE progenitors, whereas the remaining three are seen in the postmitotic mantle zone. Relative expression levels are altered and regional distinctions are lost for each gene in LGE or MGE cells propagated as neurospheres, indicating that these newly identified molecular characteristics of LGE or MGE progenitors depend on forebrain signals not available in the neurosphere assay. Analyses of Pax6(Sey/Sey), Shh(-/-), and Gli3(XtJ/XtJ) mutants suggests that LGE and MGE progenitor identity does not rely exclusively on previously established forebrain-intrinsic patterning mechanisms. Among a limited number of additional potential patterning mechanisms, we found that extrinsic signals from the frontonasal mesenchyme are essential for Shh- and Fgf8-dependent regulation of LGE and MGE genes. Thus, extrinsic and intrinsic forebrain patterning mechanisms cooperate to establish LGE and MGE progenitor identity, and presumably their capacities to generate distinct classes of neuronal progeny.


Assuntos
Padronização Corporal/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Neurônios/metabolismo , Células-Tronco/metabolismo , Telencéfalo/embriologia , Telencéfalo/metabolismo , Proteínas ADAM/genética , Proteína ADAMTS5 , Animais , Células Cultivadas , Feminino , Fator 8 de Crescimento de Fibroblasto/genética , Proteínas Hedgehog/genética , Fator de Transcrição Ikaros/genética , Imunoglobulina G/genética , Masculino , Metilglicosídeos/genética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas-G/genética , Células-Tronco/citologia , Frações Subcelulares , Telencéfalo/citologia
18.
Mamm Genome ; 17(8): 822-32, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16897343

RESUMO

Non-Mendelian factors may influence central nervous system (CNS) phenotypes in patients with 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velocardiofacial Syndrome), and similar mechanisms may operate in mice carrying a deletion of one or more 22q11 gene orthologs. Accordingly, we examined the influence of parent of origin on expression of 25 murine 22q11 orthologs in the developing and mature CNS using single nucleotide polymorphism (SNP)-based analysis in interspecific crosses and quantification of mRNA in a murine model of 22q11DS. We found no evidence for absolute genomic imprinting or silencing. All 25 genes are biallelically expressed in the developing and adult brains. Furthermore, if more subtle forms of allelic biasing are present, they are very small in magnitude and most likely beyond the resolution of currently available quantitative approaches. Given the high degree of similarity of human 22q11 and the orthologous region of mmChr16, genomic imprinting most likely cannot explain apparent parent-of-origin effects in 22q11DS.


Assuntos
Síndrome de DiGeorge/genética , Impressão Genômica/genética , Alelos , Animais , Cruzamentos Genéticos , Feminino , Deleção de Genes , Expressão Gênica , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único , Homologia de Sequência
19.
Dev Biol ; 297(2): 387-401, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16790240

RESUMO

We defined the cellular mechanisms for genesis, migration, and differentiation of the initial population of olfactory bulb (OB) interneurons. This cohort of early generated cells, many of which become postmitotic on embryonic day (E) 14.5, differentiates into a wide range of mature OB interneurons by postnatal day (P) 21, and a substantial number remains in the OB at P60. Their precursors autonomously acquire a distinct identity defined by their position in the lateral ganglionic eminence (LGE). The progeny migrate selectively to the OB rudiment in a pathway that presages the rostral migratory stream. After arriving in the OB rudiment, these early generated cells acquire cellular and molecular hallmarks of OB interneurons. Other precursors--including those from the medial ganglionic eminence (MGE) and OB--fail to generate neuroblasts with similar migratory capacity when transplanted to the LGE. The positional identity and migratory specificity of the LGE precursors is rigidly established between E12.5 and E14.5. Thus, the pioneering population of OB interneurons is generated from spatially and temporally determined LGE precursors whose progeny uniquely recognize a distinct migratory trajectory.


Assuntos
Interneurônios/metabolismo , Bulbo Olfatório/embriologia , Animais , Movimento Celular , Embrião de Mamíferos/fisiologia , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Prosencéfalo/patologia , Estrutura Terciária de Proteína , Telencéfalo/metabolismo , Fatores de Tempo
20.
Dev Dyn ; 234(3): 464-81, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16193510

RESUMO

Non-axial mesenchymal/epithelial (M/E) induction guides peripheral olfactory pathway differentiation using cellular and molecular mechanisms similar to those in the developing limbs, aortic arches, and branchial arches. At each of these bilaterally symmetric sites off the midline axis, a thickened ectodermal epithelium is apposed to a specialized mesenchyme derived largely, but not exclusively, from the neural crest. The capacity of M/E interaction in the olfactory primordia (the combined olfactory placodal epithelium and adjacent mesenchyme) to induce a distinct class of sensory receptor neurons-olfactory receptor neurons-suggests that this mechanism has been modified to accommodate neurogenesis, neurite outgrowth, and axon guidance, in addition to musculoskeletal differentiation, chondrogenesis, and vasculogenesis. Accordingly, although the olfactory primordia share signaling molecules and transcriptional regulators with other bilaterally symmetric, non-axial sites such as limb buds, their activity may be adapted to mediate distinct aspects of cellular differentiation and process outgrowth during the initial assembly of a sensory pathway-the primary olfactory pathway-during early forebrain development.


Assuntos
Diferenciação Celular , Morfogênese , Neurônios/citologia , Nariz/citologia , Nariz/embriologia , Condutos Olfatórios/citologia , Condutos Olfatórios/embriologia , Animais , Regulação da Expressão Gênica no Desenvolvimento , Mucosa Nasal/metabolismo , Neurônios/metabolismo
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