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1.
J Neurosci ; 40(15): 2976-2992, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32152201

RESUMO

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39 However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.


Assuntos
Cóclea/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/genética , Perda Auditiva Neurossensorial/genética , Fator de Crescimento de Hepatócito/genética , Crista Neural/crescimento & desenvolvimento , Estria Vascular/patologia , Animais , Contagem de Células , Orelha Interna/anormalidades , Feminino , Células Ciliadas Auditivas , Perda Auditiva Neurossensorial/patologia , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Crista Neural/patologia , Sondas RNA
2.
Glia ; 68(7): 1329-1346, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31696982

RESUMO

Cells of the oligodendrocyte (OLG) lineage engage in highly motile behaviors that are crucial for effective central nervous system (CNS) myelination. These behaviors include the guided migration of OLG progenitor cells (OPCs), the surveying of local environments by cellular processes extending from differentiating and pre-myelinating OLGs, and during the process of active myelin wrapping, the forward movement of the leading edge of the myelin sheath's inner tongue along the axon. Almost all of these motile behaviors are driven by actin cytoskeletal dynamics initiated within a lamellipodial structure that is located at the tip of cellular OLG/OPC processes and is structurally as well as functionally similar to the neuronal growth cone. Accordingly, coordinated stoichiometries of actin filament (F-actin) assembly and disassembly at these OLG/OPC growth cones have been implicated in directing process outgrowth and guidance, and the initiation of myelination. Nonetheless, the functional importance of the OLG/OPC growth cone still remains to be fully understood, and, as a unique aspect of actin cytoskeletal dynamics, F-actin depolymerization and disassembly start to predominate at the transition from myelination initiation to myelin wrapping. This review provides an overview of the current knowledge about OLG/OPC growth cones, and it proposes a model in which actin cytoskeletal dynamics in OLG/OPC growth cones are a main driver for morphological transformations and motile behaviors. Remarkably, these activities, at least at the later stages of OLG maturation, may be regulated independently from the transcriptional gene expression changes typically associated with CNS myelination.


Assuntos
Movimento Celular/fisiologia , Sistema Nervoso Central/metabolismo , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/citologia , Oligodendroglia/metabolismo , Animais , Humanos , Células-Tronco/citologia
3.
Neurochem Res ; 45(3): 551-560, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628017

RESUMO

Glutamate, the main excitatory neurotransmitter of the vertebrate central nervous system (CNS), is well known as a regulator of neuronal plasticity and neurodevelopment. Such glutamate function is thought to be mediated primarily by signaling through glutamate receptors. Thus, it requires a tight regulation of extracellular glutamate levels and a fine-tuned homeostasis that, when dysregulated, has been associated with a wide range of central pathologies including neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. In the mammalian CNS, extracellular glutamate levels are controlled by a family of sodium-dependent glutamate transporters belonging to the solute carrier family 1 (SLC1) that are also referred to as excitatory amino acid transporters (EAATs). The presumed main function of EAATs has been best described in the context of synaptic transmission where EAATs expressed by astrocytes and neurons effectively regulate extracellular glutamate levels so that synapses can function independently. There is, however, increasing evidence that EAATs are expressed by cells other than astrocytes and neurons, and that they exhibit functions beyond glutamate clearance. In this review, we will focus on the expression and functions of EAATs in the myelinating cells of the CNS, oligodendrocytes. More specifically, we will discuss potential roles of oligodendrocyte-expressed EAATs in contributing to extracellular glutamate homeostasis, and in regulating oligodendrocyte maturation and CNS myelination by exerting signaling functions that have traditionally been associated with glutamate receptors. In addition, we will provide some examples for how dysregulation of oligodendrocyte-expressed EAATs may be involved in the pathophysiology of neurologic diseases.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Ácido Glutâmico/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Oligodendroglia/metabolismo , Sinapses/fisiologia , Animais , Humanos , Transmissão Sináptica
4.
Dev Psychobiol ; 58(3): 303-14, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26497119

RESUMO

Positive father involvement is associated with positive child outcomes. There is great variation in fathers' involvement and fathering behaviors, and men's testosterone (T) has been proposed as a potential biological contributor to paternal involvement. Previous studies investigating testosterone changes in response to father-infant interactions or exposure to infant cues were unclear as to whether individual variation in T is predictive of fathering behavior. We show that individual variation in fathers' T reactivity to their infants during a challenging laboratory paradigm (Strange Situation) uniquely predicted fathers' positive parenting behaviors during a subsequent father-infant interaction, in addition to other psychosocial determinants of paternal involvement, such as dispositional empathy and marital quality. The findings have implications for understanding fathering behaviors and how fathers can contribute to their children's socioemotional development.


Assuntos
Relações Pai-Filho , Individualidade , Poder Familiar , Comportamento Paterno/fisiologia , Testosterona/metabolismo , Adulto , Feminino , Humanos , Lactente , Masculino
5.
Depress Anxiety ; 32(2): 141-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24890938

RESUMO

BACKGROUND: Perinatal depression negatively impacts women, parenting, and children's development. However, not much is known about maternal specific beliefs that may be associated with perinatal depression. We created a new measure that examined the rigidity of perinatal women's beliefs in three major domains suggested to be closely related to mood and behavior: anticipated maternal self-efficacy, perceptions of child vulnerability, and perceptions of societal expectations of mothers (PSEM). METHODS: A 26-item measure (the Rigidity of Maternal Beliefs Scale, RMBS) was developed and completed by women at two time points, pregnancy (n = 134) and postpartum (n = 113), along with the Edinburgh Postnatal Depression Scale. Exploratory factor analysis (EFA) examined the factor structure of the RMBS and validity and reliability were also tested. RESULTS: The EFA suggested that a four-factor solution was most interpretable, with few items cross-loading, and there were common themes that unified the items in each factor, resulting in a 24-item final measure. Cronbach's alpha confirmed the internal consistency, whereas bivariate correlations revealed the measure had good test-retest reliability, discriminant validity, and convergent validity. Regression analyses established predictive validity of the RMBS for postpartum depressive symptoms. CONCLUSIONS: The RMBS may be useful with clinical populations to identify maladaptive or rigid thoughts that could be a focus of intervention. This tool may also be used to guide conversation about motherhood expectations within any context where pregnant women present (e.g., prenatal care, social services), as well as potentially identifying women who are at risk for postpartum depression in clinical contexts.


Assuntos
Depressão Pós-Parto/psicologia , Depressão/psicologia , Poder Familiar/psicologia , Período Periparto/psicologia , Autorrelato/normas , Adulto , Criança , Depressão Pós-Parto/diagnóstico , Análise Fatorial , Feminino , Humanos , Masculino , Período Pós-Parto , Gravidez , Reprodutibilidade dos Testes , Autoeficácia
7.
Front Cell Neurosci ; 16: 905299, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35722615

RESUMO

The sodium-dependent glutamate transporter GLT-1 (EAAT2, SLC1A2) has been well-described as an important regulator of extracellular glutamate homeostasis in the central nervous system (CNS), a function that is performed mainly through its presence on astrocytes. There is, however, increasing evidence for the expression of GLT-1 in CNS cells other than astrocytes and in functional roles that are mediated by mechanisms downstream of glutamate uptake. In this context, GLT-1 expression has been reported for both neurons and oligodendrocytes (OLGs), and neuronal presynaptic presence of GLT-1 has been implicated in the regulation of glutamate uptake, gene expression, and mitochondrial function. Much less is currently known about the functional roles of GLT-1 expressed by OLGs. The data presented here provide first evidence that GLT-1 expressed by maturing OLGs contributes to the modulation of developmental myelination in the CNS. More specifically, using inducible and conditional knockout mice in which GLT-1 was deleted in maturing OLGs during a peak period of myelination (between 2 and 4 weeks of age) revealed hypomyelinated characteristics in the corpus callosum of preferentially male mice. These characteristics included reduced percentages of smaller diameter myelinated axons and reduced myelin thickness. Interestingly, this myelination phenotype was not found to be associated with major changes in myelin gene expression. Taken together, the data presented here demonstrate that GLT-1 expressed by maturing OLGs is involved in the modulation of the morphological aspects associated with CNS myelination in at least the corpus callosum and during a developmental window that appears of particular vulnerability in males compared to females.

8.
Infant Behav Dev ; 37(3): 406-15, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24956500

RESUMO

Despite the consistent link between parenting stress and postpartum depressive symptoms, few studies have explored the relationships longitudinally. The purpose of this study was to test bidirectional and unidirectional models of depressive symptoms and parenting stress. Uniquely, three specific domains of parenting stress were examined: parental distress, difficult child stress, and parent-child dysfunctional interaction (PCDI). One hundred and five women completed the Beck Depression Inventory and the Parenting Stress Index - Short Form at 3, 7, and 14 months after giving birth. Structural equation modeling revealed that total parenting stress predicted later depressive symptoms, however, there were different patterns between postpartum depressive symptoms and different types of parenting stress. A unidirectional model of parental distress predicting depressive symptoms best fit the data, with significant stability paths but non-significant cross-lagged paths. A unidirectional model of depressive symptoms predicted significant later difficult child stress. No model fit well with PCDI. Future research should continue to explore the specific nature of the associations of postpartum depression and different types of parenting stress on infant development and the infant-mother relationship.


Assuntos
Depressão Pós-Parto/psicologia , Relações Mãe-Filho/psicologia , Poder Familiar/psicologia , Estresse Psicológico/psicologia , Adulto , Desenvolvimento Infantil , Depressão Pós-Parto/diagnóstico , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Modelos Estatísticos , Escalas de Graduação Psiquiátrica
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