RESUMO
GALNT17 encodes a N-acetylgalactosaminyltransferase (GalNAc-T) protein specifically involved in mucin-type O-linked glycosylation of target proteins, a process important for cell adhesion, cell signaling, neurotransmitter activity, neurite outgrowth, and neurite sensing. GALNT17, also known as WBSCR17, is located at the edge of the Williams-Beuren Syndrome (WBS) critical region and adjacent to the AUTS2 locus, genomic regions associated with neurodevelopmental phenotypes that are thought to be co-regulated. Although previous data have implicated Galnt17 in neurodevelopment, the in vivo functions of this gene have not been investigated. In this study, we have analyzed behavioral, brain pathology, and molecular phenotypes exhibited by Galnt17 knockout (Galnt17-/-) mice. We show that Galnt17-/- mutants exhibit developmental neuropathology within the cerebellar vermis, along with abnormal activity, coordination, and social interaction deficits. Transcriptomic and protein analysis revealed reductions in both mucin type O-glycosylation and heparan sulfate synthesis in the developing mutant cerebellum along with disruption of pathways central to neuron differentiation, axon pathfinding, and synaptic signaling, consistent with the mutant neuropathology. These brain and behavioral phenotypes and molecular data confirm a specific role for Galnt17 in brain development and suggest new clues to factors that could contribute to phenotypes in certain WBS and AUTS2 syndrome patients.
Assuntos
Vermis Cerebelar , N-Acetilgalactosaminiltransferases , Animais , Camundongos , Encéfalo/metabolismo , Vermis Cerebelar/metabolismo , Cerebelo/metabolismo , Mucinas/metabolismo , N-Acetilgalactosaminiltransferases/metabolismo , Proteínas/metabolismo , Interação Social , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
Neuronal networks are the standard heuristic model today for describing brain activity associated with animal behavior. Recent studies have revealed an extensive role for a completely distinct layer of networked activities in the brain-the gene regulatory network (GRN)-that orchestrates expression levels of hundreds to thousands of genes in a behavior-related manner. We examine emerging insights into the relationships between these two types of networks and discuss their interplay in spatial as well as temporal dimensions, across multiple scales of organization. We discuss properties expected of behavior-related GRNs by drawing inspiration from the rich literature on GRNs related to animal development, comparing and contrasting these two broad classes of GRNs as they relate to their respective phenotypic manifestations. Developmental GRNs also represent a third layer of network biology, playing out over a third timescale, which is believed to play a crucial mediatory role between neuronal networks and behavioral GRNs. We end with a special emphasis on social behavior, discuss whether unique GRN organization and cis-regulatory architecture underlies this special class of behavior, and review literature that suggests an affirmative answer.
Assuntos
Comportamento , Encéfalo/fisiologia , Redes Reguladoras de Genes , Animais , Encéfalo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , HumanosRESUMO
Adults of many species will care for young offspring that are not their own, a phenomenon called alloparenting. However, in many cases, nonparental adults must be sensitized by repeated or extended exposures to newborns before they will robustly display parental-like behaviors. To capture neurogenomic events underlying the transition to active parental caring behaviors, we analyzed brain gene expression and chromatin profiles of virgin female mice co-housed with pregnant dams during pregnancy and after birth. After an initial display of antagonistic behaviors and a surge of defense-related gene expression, we observed a dramatic shift in the chromatin landscape specifically in amygdala of the pup-exposed virgin females compared to females co-housed with mother before birth, accompanied by a dampening of anxiety-related gene expression. This epigenetic shift coincided with hypothalamic expression of the oxytocin gene and the emergence of behaviors and gene expression patterns classically associated with maternal care. The results outline a neurogenomic program associated with dramatic behavioral changes and suggest molecular networks relevant to human postpartum mental health.
Assuntos
Tonsila do Cerebelo/metabolismo , Comportamento Animal/fisiologia , Epigênese Genética , Comportamento Materno/fisiologia , Proteínas do Tecido Nervoso/genética , Ocitocina/genética , Animais , Animais Recém-Nascidos , Ansiedade/psicologia , Cromatina/química , Cromatina/metabolismo , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Hipotálamo/metabolismo , Comportamento Materno/psicologia , Camundongos , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Ocitocina/metabolismo , Gravidez , Abstinência SexualRESUMO
Social interactions can be divided into two categories, affiliative and agonistic. How neurogenomic responses reflect these opposing valences is a central question in the biological embedding of experience. To address this question, we exposed honey bees to a queen larva, which evokes nursing, an affiliative alloparenting interaction, and measured the transcriptomic response of the mushroom body brain region at different times after exposure. Hundreds of genes were differentially expressed at distinct time points, revealing a dynamic temporal patterning of the response. Comparing these results to our previously published research on agonistic aggressive interactions, we found both shared and unique transcriptomic responses to each interaction. The commonly responding gene set was enriched for nuclear receptor signaling, the set specific to nursing was enriched for olfaction and neuron differentiation, and the set enriched for aggression was enriched for cytoskeleton, metabolism, and chromosome organization. Whole brain histone profiling after the affiliative interaction revealed few changes in chromatin accessibility, suggesting that the transcriptomic changes derive from already accessible areas of the genome. Although only one stimulus of each type was studied, we suggest that elements of the observed transcriptomic responses reflect molecular encoding of stimulus valence, thus priming individuals for future encounters. This hypothesis is supported by behavioral analyses showing that bees responding to either the affiliative or agonistic stimulus exhibited a higher probability of repeating the same behavior but a lower probability of performing the opposite behavior. These findings add to our understanding of the biological embedding at the molecular level.
Assuntos
Comportamento Agonístico , Abelhas/genética , Comportamento Cooperativo , Transcriptoma , Animais , Abelhas/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , AprendizagemRESUMO
Progesterone, acting through the progesterone receptors (PGRs), is one of the most critical regulators of endometrial differentiation, known as decidualization, which is a key step toward the establishment of pregnancy. Yet a long-standing unresolved issue in uterine biology is the precise roles played by the major PGR isoforms, PGR-A and PGR-B, during decidualization in the human. Our approach, expressing PGR-A and PGR-B individually after silencing endogenous PGRs in human endometrial stromal cells (HESCs), enabled the analysis of the roles of these isoforms separately as well as jointly. Chromatin immunoprecipitation-sequencing in combination with gene expression profiling revealed that PGR-B controls a substantially larger cistrome and transcriptome than PGR-A during HESC differentiation. Interestingly, PGR-B directly regulates the expression of PGR-A. De novo motif analysis indicated that, although the 2 isoforms bind to the same DNA sequence motif, there are both common and unique neighboring motifs where other transcription factors, such as FOSL1/2, JUN, C/EBPß, and STAT3, bind and dictate the transcriptional activities of these isoforms. We found that PGR-A and PGR-B regulate overlapping as well as distinct sets of genes, many of which are known to be critical for decidualization and establishment of pregnancy. When PGR-A and PGR-B were coexpressed during HESC differentiation, PGR-B played a predominant role, although both isoforms influenced each other's transcriptional activity. This study revealed the gene networks that operate downstream of each PGR isoform to mediate critical functions, such as regulation of the cell cycle, angiogenesis, lysosomal activation, insulin receptor signaling, and apoptosis, during decidualization in the human.
Assuntos
Decídua/metabolismo , Receptores de Progesterona/metabolismo , Sequência de Bases , Sítios de Ligação , Ciclo Celular , Diferenciação Celular , Células/citologia , Decídua/irrigação sanguínea , Decídua/citologia , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genoma Humano , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Dados de Sequência Molecular , Neovascularização Fisiológica , Motivos de Nucleotídeos/genética , Gravidez , Ligação Proteica , Isoformas de Proteínas/metabolismo , Reprodutibilidade dos TestesRESUMO
Increased susceptibility to gastric cancer has been associated with a wide range of host genetic and environmental factors, including Helicobacter pylori infection. Helicobacter pylori infection is postulated to initiate a progression through atrophic gastritis, metaplasia and dysplasia to cancer, and has been associated with reduction of acid output and dysregulation of stomach mucins. Here, we present the characterization of two mouse lines carrying mutant alleles of the gene encoding the Kcnq1 potassium channel, which very rapidly establish chronic gastritis in a pathogen-exposed environment. These mice develop gastric hyperplasia, hypochlorhydria and mucin dysregulation independent of infection. Metaplasia, dysplasia and pre-malignant adenomatous hyperplasia of the stomach have been observed in these Kcnq1 mutant mice, also independent of infection. The data presented here suggest that Kcnq1 mutant mice can be used both as an efficient model for the development of atrophic gastritis after infection and to determine the processes during the later stages of progression to gastric cancer independent of infection. Thus, Kcnq1 mutant mice are a powerful new tool for investigating the connection between acid balance, Helicobacter infection and mucin disruption in the progression to gastric cancer.