Publications

Abstract

Comparative neurobiology allows us to investigate relationships between phylogeny and the brain and understand the evolution of traits. Bats constitute an attractive group of mammalian species for comparative studies, given their large diversity in behavioural phenotypes, brain morphology, and array of specialised traits. Currently, the order Chiroptera contains over 1,450 species within 21 families and spans ca. 65 million years of evolution. To date, 194 Neotropical bat species (ca. 13% of the total number of species around the world) have been recorded in Central America. This study includes qualitative and quantitative macromorphological descriptions of the brains of 12 species from six families of Neotropical bats. These analyses, which include histological neuronal staining of two species from different families (Phyllostomus hastatus and Saccopteryx bilineata), show substantial diversity in brain macromorphology including brain shape and size, exposure of mesencephalic regions, and cortical and cerebellar fissure depth. Brain macromorphology can in part be explained by phylogeny as species within the same family are more similar to each other. However, macromorphology cannot be explained by evolutionary time alone as brain differences between some phyllostomid bats are larger than between species from the family Emballonuridae despite being of comparable diverging distances in the phylogenetic tree. This suggests that faster evolutionary changes in brain morphology occurred in phyllostomids — although a larger number of species needs to be studied to confirm this. Our results show the rich diversity in brain morphology that bats provide for comparative and evolutionary studies.

Abstract

We present a reference genome assembly from an individual male Rhynchonycteris naso (Chordata; Mammalia; Chiroptera; Emballonuridae). The genome sequence is 2.46 Gb in span. The majority of the assembly is scaffolded into 22 chromosomal pseudomolecules, with the Y sex chromosome assembled.

Abstract

We describe here the first characterization of the genome of the bat Pteronotus mexicanus, an endemic species of Mexico, as part of the Mexican Bat Genome Project which focuses on the characterization and assembly of the genomes of endemic bats in Mexico. The genome was assembled from a liver tissue sample of an adult male from Jalisco, Mexico provided by the Texas Tech University Museum tissue collection. The assembled genome size was 1.9 Gb. The assembly of the genome was fitted in a framework of 110,533 scaffolds and 1,659,535 contigs. The ecological importance of bats such as P. mexicanus, and their diverse ecological roles, underscores the value of having complete genomes in addressing information gaps and facing challenges regarding their function in ecosystems and their conservation.

Abstract

Retinoic acid-related orphan receptor alpha gene (RORa) and the microRNA MIR137 have both recently been identified as novel candidate genes for neuropsychiatric disorders. RORa encodes a ligand-dependent orphan nuclear receptor that acts as a transcriptional regulator and miR-137 is a brain enriched small non-coding RNA that interacts with gene transcripts to control protein levels. Given the mounting evidence for RORa in autism spectrum disorders (ASD) and MIR137 in schizophrenia and ASD, we investigated if there was a functional biological relationship between these two genes. Herein, we demonstrate that miR-137 targets the 3'UTR of RORa in a site specific manner. We also provide further support for MIR137 as an autism candidate by showing that a large number of previously implicated autism genes are also putatively targeted by miR-137. This work supports the role of MIR137 as an ASD candidate and demonstrates a direct biological link between these previously unrelated autism candidate genes

Abstract

FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells

Abstract

The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions

Abstract

The fruitless gene (fru) encodes a set of transcription factors (Fru) that display sexually dimorphic gene expression in the brain of the fruit-fly;Drosophila melanogaster . Behavioural studies have demonstrated that fru isessentialforcourtshipbehaviour inthemale flyandisthoughttoact bydirectingthe development of sex-specific neural circuitry that encodes this innate behavioural response. This study reports the identification of direct regulatory targets of the sexually dimorphic isoforms of the Fru protein using an in vitro model system. Genome wide binding sites were identified for each of the isoforms using Chromatin Immunoprecipitation coupled to deep sequencing (ChIP-Seq). Putative target genes were found to be involved in processes such as neurotransmission, ion-channel signalling and neuron development. All isoforms showed asignificant bias towards genes located on the X-chromosome,which may reflect a specific role for Fru in regulating x-linked genes. Taken together with expression analysis carried out in Fru positive neurons specifically isolated from the male fly brain, it appears that the Fru protein acts as a transcriptional activator. Understanding the regulatory cascades induced by Fru will help to shed light on the molecular mechanisms that are important for specification of neural circuitry underlying complex behaviour

Abstract

Purpose: Factors affecting the efficacy of therapeutic monoclonal antibodies (mAb) directed to the epidermal growth factor receptor (EGFR) remain relatively unknown, especially in glioma. Experimental Design: We examined the efficacy of two EGFR-specific mAbs (mAbs 806 and 528) against U87MG-derived glioma xenografts expressing EGFR variants. Using this approach allowed us to change the form of the EGFR while keeping the genetic background constant. These variants included the de2-7 EGFR (or EGFRvIII), a constitutively active mutation of the EGFR expressed in glioma. Results: The efficacy of the mAbs correlated with EGFR number; however, the most important factor was receptor activation. Whereas U87MG xenografts expressing the de2-7 EGFR responded to therapy, those exhibiting a dead kinase de2-7 EGFR were refractory. A modified de2-7 EGFR that was kinase active but autophosphorylation deficient also responded, suggesting that these mAbs function in de2-7 EGFR–expressing xenografts by blocking transphosphorylation. Because de2-7 EGFR–expressing U87MG xenografts coexpress the wild-type EGFR, efficacy of the mAbs was also tested against NR6 xenografts that expressed the de2-7 EGFR in isolation. Whereas mAb 806 displayed antitumor activity against NR6 xenografts, mAb 528 therapy was ineffective, suggesting that mAb 528 mediates its antitumor activity by disrupting interactions between the de2-7 and wild-type EGFR. Finally, genetic disruption of Src in U87MG xenografts expressing the de2-7 EGFR dramatically enhanced mAb 806 efficacy. Conclusions: The effective use of EGFR-specific antibodies in glioma will depend on identifying tumors with activated EGFR. The combination of EGFR and Src inhibitors may be an effective strategy for the treatment of glioma.

Abstract

Mutations in FOXP2, a member of the forkhead family of transcription factor genes, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain, therefore, provides a unique tool with which to explore the development of human language and speech. Here, we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) by use of chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in BG and IFC indicates a core set of 34 transcriptional targets of FOXP2. We identified targets specific to IFC or BG that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of central nervous system patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study to use human brain tissue, making the FOXP2-target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes.

Abstract

We previously discovered that mutations of the human FOXP2 gene cause a monogenic communication disorder, primarily characterized by difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech. Affected people have deficits in expressive and receptive linguistic processing and display structural and/or functional abnormalities in cortical and subcortical brain regions. FOXP2 provides a unique window into neural processes involved in speech and language. In particular, its role as a transcription factor gene offers powerful functional genomic routes for dissecting critical neurogenetic mechanisms. Here, we employ chromatin immunoprecipitation coupled with promoter microarrays (ChIP-chip) to successfully identify genomic sites that are directly bound by FOXP2 protein in native chromatin of human neuron-like cells. We focus on a subset of downstream targets identified by this approach, showing that altered FOXP2 levels yield significant changes in expression in our cell-based models and that FOXP2 binds in a specific manner to consensus sites within the relevant promoters. Moreover, we demonstrate significant quantitative differences in target expression in embryonic brains of mutant mice, mediated by specific in vivo Foxp2-chromatin interactions. This work represents the first identification and in vivo verification of neural targets regulated by FOXP2. Our data indicate that FOXP2 has dual functionality, acting to either repress or activate gene expression at occupied promoters. The identified targets suggest roles in modulating synaptic plasticity, neurodevelopment, neurotransmission, and axon guidance and represent novel entry points into in vivo pathways that may be disturbed in speech and language disorders.