Cognitive abilities vary among people. About 40–50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ...ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) – the ability to reason in novel situations – and general crystallized intelligence (gC) – the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome‐wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene‐ and pathway‐based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long‐term depression (LTD) seemed to underlie gC. Thus, this study supports the gF–gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.
GWAS‐based pathway analysis differentiates between fluid and crystallized intelligence (
gF and
gC).
Premature ovarian failure (POF) affects ∼1% of women and is known to be caused by sex chromosome abnormalities, iatrogenic agents and autoimmune diseases, but in the majority of cases the cause is ...unknown. However, several families have been identified as having an inherited predisposition to POF, suggesting a genetic component to the condition in these cases. The FOXL2 gene of 70 POF patients from New Zealand and Slovenia was screened for mutations. In a Slovenian POF patient, a novel 30 bp deletion was identified that was predicted to remove 10 out of 14 alanines (A221_A230del), from the polyalanine tract downstream of the winged helix/forkhead domain of the FOXL2 protein. A novel single nucleotide substitution, 772(1009)T>A, which is predicted to change amino acid 258 from tyrosine to asparagine (Y258N), was identified in a New Zealand POF patient. Neither mutation was identified in 200 normal control chromosomes from 100 control samples. Three previously unreported single nucleotide substitutions, considered to be non-functional polymorphisms, were also identified.
Studies in several cell types indicate that the actions of integrin receptors for extracellular matrix and receptors for growth factors are synergistic in regulating cellular differentiation and ...function. We studied the roles of the α1β1 and α2β1 integrin collagen receptors in regulating the differentiation of 2T3 osteoblastic cells in response to bone morphogenetic protein (BMP)‐2. The immortalized 2T3 cell line was established from the calvaria of mice transgenic for a BMP‐2 promoter driving SV40 T‐antigen. These cells require exogenous BMP‐2, as well as ascorbic acid and β‐glycerolphosphate, for expression of a mature osteoblast phenotype and formation of a mineralized matrix. To determine how integrin receptors for collagen‐I affect BMP‐2 signaling, function‐perturbing anti‐rat α1 and/or α2 integrin subunit, or anti‐type I collagen (Col‐I), antibodies were added to human recombinant (hr)BMP‐2–treated 2T3 cultures at confluence (C0) or at 4 or 8 days postconfluence (C4, C8). After 4 days of exposure to the antibodies, cultures were assayed for alkaline phosphatase (ALP) mRNA levels and enzyme activity and for cAMP production in response to parathyroid hormone. Addition of anti‐Collagen‐I or both anti–integrin‐α1 and ‐α2 antibodies to C0 cultures blocked expression of these early osteoblast markers by more than 90%, and also blocked mineralization (0.5–1.8% control) of these cells. In all cases, adding anti‐α1 or anti‐α2 antibodies separately produced partial effects, while their combined effect approached that of anti‐Collagen‐I. When antibodies were added to more differentiated 2T3 cells, the inhibitory effects decreased. 2T3 cells carrying constitutively active BMP receptor (caBMPR‐IB) showed elevated ALP activity without hrBMP‐2; this constitutive activity was also suppressed by α1 and α2 integrin antibodies and by anti‐Col‐I antibody. Together, our data suggest that a signal(s) from collagen integrin receptors regulates the response to BMP downstream of BMPR‐IB and upstream of the regulation of ALP mRNA and other early markers of osteoblast differentiation.
OBJECTIVE: The 22q11.2 deletion syndrome (DiGeorge velocardiofacial syndrome) is associated with attentional problems and executive dysfunction, and is one of the highest known risk factors for ...schizophrenia. These behavioral manifestations of 22q11.2 deletion syndrome could result from haploinsufficiency of the catechol O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype as a predictor of prefrontal cognitive function in patients with 22q11.2 deletion syndrome. METHOD: Patients with confirmed 22q11.2 deletions (N=44) underwent neurocognitive testing following Val158Met genotyping (Met hemizygous: N=16; Val hemizygous: N=28). RESULTS: Analyses of covariance revealed that Met-hemizygous patients performed significantly better on a composite measure of executive function (comprising set-shifting, verbal fluency, attention, and working memory) than did Val-hemizygous patients. CONCLUSIONS: These data are consistent with those of previous studies in normal individuals, suggesting that a functional genetic polymorphism in the 22q11 region may influence prefrontal cognition in individuals with COMT haploinsufficiency.
This presentation will focus on using microarray data on a clonal osteoblast cell model to analyze the early BMP-2 responsive genes, as well as some of the later genes regulated by BMP2 during ...different phases of mineralization. We will focus on the early phases of gene expression that occur after BMP2 signaling from 30 min up to 1 day. The hypothesis is that understanding how these early genes are regulated during the initial multilayering and growth phase of osteoblasts will lead to models of how BMP activity stimulates cell growth, cell migration, multilayering, matrix deposition and remodeling phase that allows subsequent mineralization. The Dlx2 and Dlx5 homeobox genes have been shown to be critical for bone formation both in vitro and in vivo. Both Dlx 2 and Dlx5 are activated within 15-30 minutes after BMP2 addition to the mouse 2T3 osteoblast model and primary fetal rat calvarial osteoblasts. The Dlx2 and Dlx5 genes stay elevated in the presence of BMP2 for up to 5 days, a time when overt mineralization is just beginning. To understand the genomic network that Dlx5 and Dlx2 regulate at the transcription level, we have taken an approach where we use a specific transcription repressor protein, Engrailed, ligated to the Dlx5 homeodomain. The idea is that this Eng-Dlx5 protein will interact with Dlx5 and possibly Dlx2 and related Dlx- regulated genes in vivo and down-regulate their transcriptional initiation. Using a microarray approach with over 5,000 known genes we can identify the genes that are directly and indirectly regulated by Dlx5 and Dlx2. This will allow us to build an initial genomic network of Dlx- regulated genes at the transcriptional level. We will present our model and preliminary efforts at understanding the genomic network regulated by this important BMP2-regulated transcription factor class in osteoblast biology.
Estrogens exert their physiological effects on target tissues by interacting with the estrogen receptors, ERα and ERβ. Estrogen replacement is one the most common and effective strategies used to ...prevent osteoporosis in postmenopausal women. Whereas it was thought that estrogens work exclusively by inhibiting bone resorption, our previous results show that 17β-estradiol (E2) increases mouse bone morphogenetic protein (BMP)-2 mRNA, suggesting that estrogens may also enhance bone formation. In this study, we used quantitative real-time RT-PCR analysis to demonstrate that estrogens increase BMP-2 mRNA in mouse mesenchymal stem cells. The selective ER modulators, tamoxifen, raloxifene, and ICI-182,780 (ICI), failed to enhance BMP-2 mRNA, whereas ICI inhibited E2 stimulation of expression. To investigate if estrogens increase BMP-2 expression by transcriptional mechanisms and if the response is mediated by ERα and/or ERβ, we studied the effects of estrogens on BMP-2 promoter activity in transient transfected C3H10T1/2 cells. E2 produced a dose-dependent induction of the mouse −2712 BMP-2 promoter activity in cells cotransfected with ERα and ERβ. At a dose of 10 nm E2, ERα induced mouse BMP-2 promoter activity 9-fold, whereas a 3-fold increase was observed in cells cotransfected with ERβ. Tamoxifen and raloxifene were weak activators of the mouse BMP-2 promoter via ERα, but not via ERβ. ICI blocked the activation of BMP-2 promoter activity by E2 acting via both ERα and ERβ, indicating that mouse BMP-2 promoter activation is ER dependent. In contrast to E2 and selective ER modulators, the phytoestrogen, genistein was more effective at activating the mouse BMP-2 promoter with ERβ, compared with ERα. Using a deletion series of the BMP-2 promoter, we determined that AP-1 or Sp1 sites are not required for E2 activation. A mutation in a sequence at −415 to −402 (5′-GGGCCActcTGACCC-3′) that resembles the classical estrogen-responsive element abolished the activation of the BMP-2 promoter in response to E2. Our studies demonstrate that E2 activation of mouse BMP-2 gene transcription requires ERα or ERβ acting via a variant estrogen-responsive element binding site in the promoter, with ERα being the more efficacious regulator. Estrogenic compounds may enhance bone formation by increasing the transcription of the BMP-2 gene.
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