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Dis Model Mech ; 15(2)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722956


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.

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


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.

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


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.

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