ABSTRACT
One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which alters the expression of IL3 by affecting the binding affinity of transcription factor SP1. Further analysis indicated that IL3 and its receptors are continuously expressed in the developing mouse brain, reaching highest levels at postnatal day 1-4. Furthermore, we found IL3 receptor alpha (IL3RA) was mainly expressed in neural progenitors and neurons, and IL3 could promote proliferation and survival of the neural progenitors. The expression level of IL3 thus played pivotal roles in the expansion and maintenance of the neural progenitor pool and the number of surviving neurons. Moreover, we found that IL3 activated both estrogen receptors, but estrogen didn't directly regulate the expression of IL3. Our results demonstrate that genetic variation in the IL3 promoter regulates human brain volume and reveals novel roles of IL3 in regulating brain development.
Subject(s)
Biomarkers, Tumor/genetics , Brain/anatomy & histology , Brain/metabolism , Interleukin-3/genetics , Neural Stem Cells/metabolism , Polymorphism, Genetic , Promoter Regions, Genetic , Receptors, Immunologic/genetics , Animals , Biomarkers, Tumor/metabolism , Cell Proliferation , Cell Survival/genetics , Female , Gene Expression Regulation , Humans , Interleukin-3/metabolism , Interleukin-3 Receptor alpha Subunit/genetics , Interleukin-3 Receptor alpha Subunit/metabolism , Male , Mice , Neural Stem Cells/cytology , Organ Size , Protein Binding , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Receptors, Immunologic/metabolism , Sex CharacteristicsABSTRACT
OBJECTIVE: GSK3ß is a key gene in neurodevelopment, and also an important target of antipsychotics. Several lines of evidence including association and gene expression studies have suggested GSK3ß as a susceptibility gene for schizophrenia, but the underlying genetic mechanism is still unknown. In this study, we test whether the genetic variants in GSK3ß contribute to the risk of schizophrenia in Chinese population. METHODS: We first conducted an association analysis of 9 representative SNPs spanning the entire genomic region of GSK3ß in two independent Han Chinese case-control samples from southwestern China (the Kunming sample and the Yuxi sample, a total of 2550 subjects).Then using EMSA and reporter gene assays, we tested the functional impact of the identified risk SNP on transcriptional factor binding affinity and promoter activity. RESULTS: We observed weak allelic associations of three GSK3ß SNPs (rs3755557, rs7431209 and rs13320980) with schizophrenia in the combined Han Chinese samples. Further analysis using genotypes (under recessive genetic model) supported the association of rs3755557 (p = 0.01, corrected), which is located in the GSK3ß promoter region. The functional assays demonstrated that the risk SNP (rs3755557) could influence the transcription factor binding affinities, resulting in a higher promoter activity of the risk allele. CONCLUSION: Our findings suggest that GSK3ß is likely a risk gene for schizophrenia, and its expression alteration caused by the risk SNP in the promoter region may contribute to the etiology of schizophrenia.
Subject(s)
Genetic Predisposition to Disease , Glycogen Synthase Kinase 3/genetics , Polymorphism, Single Nucleotide/genetics , Schizophrenia/genetics , Adult , Asian People/ethnology , Asian People/genetics , Case-Control Studies , Cell Line, Transformed , Electrophoretic Mobility Shift Assay , Female , Genetic Association Studies , Genotype , Glycogen Synthase Kinase 3 beta , Humans , Linkage Disequilibrium , Male , Middle Aged , Promoter Regions, Genetic/genetics , Schizophrenia/ethnology , TransfectionABSTRACT
OBJECTIVE: To explore the mechanisms of puncturing Shenshu point in improving osteoporosis. METHODS: Serum levels of testosterone (T) and osteocalcin (BGP) in senescence accelerated mouse prone 6 (SAMP6, test animals) and senescence accelerated mouse resistant 1 (SAMR1, for control) were determined by radioimmunoassay and their femoral biomechanical properties were determined with three-point bending test before and after puncturing to observe the effect of puncturing on the femoral biomechanical properties and bone mineral contents. RESULTS: Compared with the SAMR1 control group, the serum level of T (20.91 +/- 3.41 nmol/L) decreased (11.09 +/- 1.48 nmol/L in SAMP6 mouse), BGP (6.7 +/- 2.07 microg/L) increased (12.29 +/- 2.29 microg/L in SAMP6 mouse), femoral bending strength lowered and fragility increased. These changes were all improved to some extent or normalized, serum T level 15.05 +/- 2.63 nmol/L and BGP 8.88 +/- 1.85 microg/L after needling at Shenshu point showed significant difference when compared with those in SAMP6. CONCLUSION: Puncturing Shenshu point could effectively prevent the bone loss in SAMP6 mice, increase their bone strength, the therapeutic effect is partly by way of promoting the secretion of sex hormone, improving bone metabolism, suppressing bone transformation rate and increasing bone minerals.
