Fig 5 - uploaded by Just Genius
Content may be subject to copyright.
Reduced number of parvalbumin-positive interneurons in the hippocampus of O377 mutant mice. The cell density of parvalbuminpositive interneurons in the DG and in the ventral CA is compared between wild-type mice and O377 mutants at different ages. a, b Parvalbumin-positive GABAergic interneurons in the prefrontal cortex (pCtx) of 3-month-old wild type (a) and O377 mutant mice (b). c, d Parvalbumin-positive GABAergic interneurons in the ventral CA1 of 3-month-old wild-type (c) and O377 mutant mice (d). e, f Parvalbumin-positive GABAergic interneurons in the ventral DG of 3-month-old wild-type (e) and O377 mutant mice (f). g Cell density of
Source publication
βB2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens. This gene, however, is also expressed in several regions of the mammalian brain, although its function in this organ remains entirely unknown. To unravel some aspects of its function in the brain, we combined behavioral, neuroanatomical, and...
Contexts in source publication
Context 1
... confirm this result, we applied the thymidine analog bromodeoxyuridine (BrdU) to 3-month-old mice and quantified after a 4-week chase the number of labeled cells incorporated into the hippocampus. Again, there was no statistically significant difference between the hippo- campus of wild-type and O377 mice ( Supplementary Fig. 5), suggesting the normal generation and survival of new cells during adulthood. Next, to assess neuronal mat- uration, in the same paradigm we monitored the proportion of BrdU-positive cells expressing the postmitotic neuro- blast marker Doublecortin (DCX) and the neuronal marker NeuN (Neuronal Nuclei). ...
Context 2
... %).*p B 0.05, Student's t test, n C 4. Error bar SEM We next asked whether distinct interneuronal subpopu- lations might be altered in the hippocampus of O377 mutants. Indeed, we found that the cell density of parval- bumin-positive neurons in the ventral CA and DG of 3-month old O377 mutants was significantly lower than that in wild-type mice (Fig. 5). This is likely due to a slow process, with a decreasing trend already visible in the first postnatal weeks leading to a progressively increasing dif- ference between WT mice and mutants (Fig. 5h, i). In contrast, the parvalbumin population was not affected in the prefrontal cortex (Fig. 5g). Likewise, the density of calretinin-and ...
Context 3
... cell density of parval- bumin-positive neurons in the ventral CA and DG of 3-month old O377 mutants was significantly lower than that in wild-type mice (Fig. 5). This is likely due to a slow process, with a decreasing trend already visible in the first postnatal weeks leading to a progressively increasing dif- ference between WT mice and mutants (Fig. 5h, i). In contrast, the parvalbumin population was not affected in the prefrontal cortex (Fig. 5g). Likewise, the density of calretinin-and somatostatin-positive neurons in the pre- frontal cortex, ventral CA, and ventral DG was not sig- nificantly different between 3-month-old WT and O377 mutant mice (Supplementary Figs. 10, ...
Context 4
... was significantly lower than that in wild-type mice (Fig. 5). This is likely due to a slow process, with a decreasing trend already visible in the first postnatal weeks leading to a progressively increasing dif- ference between WT mice and mutants (Fig. 5h, i). In contrast, the parvalbumin population was not affected in the prefrontal cortex (Fig. 5g). Likewise, the density of calretinin-and somatostatin-positive neurons in the pre- frontal cortex, ventral CA, and ventral DG was not sig- nificantly different between 3-month-old WT and O377 mutant mice (Supplementary Figs. 10, ...
Context 5
... smaller size of the hippocampus might be explained at least in part by apop- tosis in the hippocampus of young mutants. Differences in apoptosis are not observed in adults, and other possible mechanisms (e.g., decreased neurogenesis or impaired neuronal maturation) are not supported by our data ( Fig. 2; Supplementary Figs. 5, 6). Increased apoptosis in the mutants might be due to the increased basal concentration of Ca 2? (Fig. 3). ...
Context 6
... apoptosis does not explain the specific loss of parvalbumin-positive interneurons in the hippo- campus of O377 mutants (Fig. 5); for this feature and its physiological consequences (increased input:output ratio in the DG), we have elaborated on another series of events; however, it may also start from the enhanced level of free Ca 2? in the mutants. The mechanisms by which the expression of Crybb2 translates into a neuronal subtype- specific phenotype might be ...
Citations
... Gene analysis of a dominant cataract mouse model unmasked a crybb2 mutation and revealed that βB2crystallin is expressed within distinct regions of the brain [22]. The Crybb2 transcript was best detected in the brain during postnatal development and through adolescence and was expressed predominantly in neurons of the olfactory bulb (mitral cell layer and glomerular layer), hippocampus (pyramidal cells of the CA1, CA2, and CA3 regions and granule cells of the dentate gyrus), cerebral cortex (pyramidal cells throughout all layers), and cerebellum (Purkinje cells and stellate cells of the molecular layers) [22,55,56]. As illustrated in animal models of optic nerve injury and axonal regeneration, mounting evidence highlights βB2-crystallin as a momentous factor that operates through autocrine and paracrine mechanisms to support axonal growth and repair, at least in part by accelerating the production of ciliary neurotrophic factor (CNTF) [49,51,57]. ...
... Mutations in the mouse Crybb2 gene give rise to alterations in prepulse inhibition (PPI; an operational measurement of sensorimotor gating) and reduce hippocampal size, i.e., features typical of patients with schizophrenia [55,93,94]. Studies in mutant Crybb2 Philly , Crybb2 Aey2 , and Crybb2 O377 mice revealed C-terminal mutations of the βB2crystallin protein, likely associated with abnormal Ca 2+ binding, which correlated with consistent alterations in adult behavior and evolution of neuropsychiatric disorders [56,93,95]. Notably, a meta-analysis of gene expression in the human cortex illustrated that the CRYBB2 gene shows the most significant association with five psychiatric disorders, namely attention-deficit hyperactivity disorder, autism, major depressive disorder, bipolar disorder, and schizophrenia [96,97]. ...
Crystallins, the major constituent proteins of mammalian lenses, are significant not only for the maintenance of eye lens stability, transparency, and refraction, but also fulfill various physiopathological functions in extraocular tissues. βB2-crystallin, for example, is a multifunctional protein expressed in the human retina, brain, testis, ovary, and multiple tumors. Mutations in the βB2 crystallin gene or denaturation of βB2-crystallin protein are associated with cataracts, ocular pathologies, and psychiatric disorders. A prominent role for βB2-crystallins in axonal growth and regeneration, as well as in dendritic outgrowth, has been demonstrated after optic nerve injury. Studies in βB2-crystallin-null mice revealed morphological and functional abnormalities in testis and ovaries, indicating βB2-crystallin contributes to male and female fertility in mice. Interestingly, although pathogenic significance remains obscure, several studies identified a clear correlation between βB2 crystallin expression and the prognosis of patients with breast cancer, colorectal cancer, prostate cancer, renal cell carcinoma, and glioblastoma in the African American population. This review summarizes the physiological and pathological functions of βB2-crystallin in the eye and other organs and tissues and discusses findings related to the expression and potential role of βB2-crystallin in tumors.
... Granulosa cells of female Crybb2(−/−) mice also exhibited reduced expression levels of cell cycle genes (Bcl-2, Cdk4 and Ccnd2) (Gao et al. 2014). In another study on the CRYBB2 mouse mutant, βB2 crystalline was reported to have a role in hippocampal function and behavioral phenotypes (Sun et al. 2013). CRYBB2 has been reported to regulate expression of different lncRNAs influencing ovarian development in mice (Gao et al. 2016). ...
The objective of this study is to discern the proteomic differences responsible for hampering the receptivity of endometrium and subduing the fertility of females with polycystic ovary syndrome in analogy to healthy fertile females. This study was designed in collaboration with Hakeem Abdul Hameed Centenary Hospital affiliated to Jamia Hamdard, New Delhi, India. Serum samples were taken from infertile PCOS subjects (n = 6) and fertile control subjects (n = 6) whereas endometrial tissue samples were recruited from ovulatory PCOS (n = 4), anovulatory PCOS (n = 4) and normal healthy fertile control subjects (n = 4) for proteomic studies. Additionally, endometrial biopsies from healthy fertile control (n = 8), PCOS with infertility (n = 6), unexplained infertility (n = 3) and endometrial hyperplasia (n = 3) were taken for validation studies. Anthropometric, biochemical and hormonal evaluation was done for all the subjects enrolled in this study. Protein profiles were generated through 2D-PAGE and differential proteins analyzed with PD-QUEST software followed by identification with MALDI-TOF MS protein mass fingerprinting. Validation of identified proteins was done through RT-PCR relative expression analysis. Protein profiling of serum revealed differential expression of proteins involved in transcriptional regulation, embryogenesis, DNA repair, decidual cell ploidy, immunomodulation, intracellular trafficking and degradation processes. Proteins involved in cell cycle regulation, cellular transport and signaling, DNA repair, apoptotic processes and mitochondrial metabolism were found to be differentially expressed in endometrium. The findings of this study revealed proteins that hold strong candidature as potential drug targets to regulate the cellular processes implicating infertility and reduced receptivity of endometrium in women with polycystic ovary syndrome.
... In mice, three mutations (Philly, Aey2, O377) have been described, all of which affect the last of the 7 exons 4,9,10 . In 2013, Sun et al. 11 first described detailed molecular, cellular, electrophysiological and behavioral alterations in βB2-crystallin deficient male O377 mutants. Compared to wildtype mice, O377 mutants displayed a decreased acoustic startle reflex (ASR) in combination with an increased prepulse inhibition (PPI). ...
... Reduced PPI has been described in patients with a first episode of schizophrenia as well as in unaffected relatives 19 and is therefore an appropriate endophenotype of schizophrenia. In addition to the deficits in sensorimotor gating, O377 mice showed a reduction of hippocampal volume, which has also been found in patients with schizophrenia 11,20 . ...
... In a previous study, increased hippocampal output was discovered in O377 mutants as determined by electrophysiological measurements. This may result in enhanced accumbal GABAergic activation, leading to increased inhibition of GABAergic neurons of the Globus pallidus, thus disinhibiting the pedunculopontine nucleus and ultimately increasing PPI 11 . In line with these data, it is tempting to speculate that polymorphic sites in CRYBB2 may be involved in the molecular pathway(s) by which CRYBB2 function affects schizophrenia-related endophenotypes. ...
βB2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens before it was detected in various brain regions of the mouse, including the hippocampus and the cerebral cortex. Mutations in the mouse Crybb2 gene lead to alterations of sensorimotor gating measured as prepulse inhibition (PPI) and reduced hippocampal size, combined with an altered number of parvalbumin-positive GABAergic interneurons. Decreased PPI and alterations of parvalbumin-positive interneurons are also endophenotypes that typically occur in schizophrenia. To verify the results found in mice, we genotyped 27 single nucleotide polymorphisms (SNPs) within the CRYBB2 gene and its flanking regions and investigated different schizophrenia typical endophenotypes in a sample of 510 schizophrenia patients and 1322 healthy controls. In the case-control study, no association with schizophrenia was found. However, 3 of the 4 investigated haplotype blocks indicated a decreased CRYBB2 mRNA expression. Two of these blocks were associated with poorer antisaccade task performance and altered working memory-linked functional magnetic resonance imaging signals. For the two haplotypes associated with antisaccade performance, suggestive evidence was found with visual memory and in addition, haplotype block 4 showed a nominally significant association with reduced sensorimotor gating, measured as P50 ratio. These results were not schizophrenia-specific, but could be detected in a combined sample of patients and healthy controls. This is the first study to demonstrate the importance of βB2-crystallin for antisaccade performance and memory function in humans and therefore provides implications for βB2-crystallin function in the human brain.
... Similarly, the gene of the major β-crystallin, Crybb2, is expressed in the testes leading to subfertility if mutated (DuPrey et al. 2007). Crybb2 is also expressed in the brain (Magabo et al. 2000;Ganguly et al. 2008), and in homozygous Crybb2 mutants, parvalbumin-positive interneurons as well as dendrites and dendritic branches in the hippocampus are decreased (Sun et al. 2013(Sun et al. , 2018, and eventually changes in schizophrenia-related endophenotypes have been observed (Heermann et al. 2018). ...
Mouse mutants are a long-lasting, valuable tool to identify genes underlying eye diseases, because the absence of eyes, very small eyes and severely affected, cataractous eyes are easily to detect without major technical equipment. In mice, actually 145 genes or loci are known for anophthalmia, 269 for microphthalmia, and 180 for cataracts. Approximately, 25% of the loci are not yet characterized; however, some of the ancient lines are extinct and not available for future research. The phenotypes of the mutants represent a continuous spectrum either in anophthalmia and microphthalmia, or in microphthalmia and cataracts. On the other side, mouse models are still missing for some genes, which have been identified in human families to be causative for anophthalmia, microphthalmia, or cataracts. Finally, the mouse offers the possibility to genetically test the roles of modifiers and the role of SNPs; these aspects open new avenues for ophthalmogenetics in the mouse.
... As part of the βγ-superfamily, evidence implicates βB2crystallin (CRYBB2) protein in lens development and adult mouse brain function [1][2][3]. Although molecular mechanisms of Crybb2 lens fiber and epithelial cell activity are established, work continues on mouse brain pleiotropic effects [4,5]. As βγ-crystallins constitute a separate class of Ca 2+ -binding Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-018-1365-5) ...
... protein (CaBP), the assumption is that CRYBB2 acts as a calcium buffer [6,7]. Nevertheless, to add further clarity, Crybb2 translation and protein transcription were investigated in the adult mouse brain [1,4]. Transcripts of Crybb2 and the encoded βB2-protein were found in several areas, e.g., in neurons of the olfactory bulb, the hippocampus, the cerebral cortex, and the cerebellum [1,4]. ...
... Nevertheless, to add further clarity, Crybb2 translation and protein transcription were investigated in the adult mouse brain [1,4]. Transcripts of Crybb2 and the encoded βB2-protein were found in several areas, e.g., in neurons of the olfactory bulb, the hippocampus, the cerebral cortex, and the cerebellum [1,4]. More specifically, we showed that approximately 97% of the cells positive for the calcium-binding protein parvalbumin (PV+ cells) co-express CRYBB2 in the mouse brain. ...
As part of the βγ-superfamily, βB2-crystallin (CRYBB2) is an ocular structural protein in the lens, and mutation of the corresponding gene can cause cataracts. CRYBB2 also is expressed in non-lens tissue such as the adult mouse brain and is associated with neuropsychiatric disorders such as schizophrenia. Nevertheless, the robustness of this association as well as how CRYBB2 may contribute to disease-relevant phenotypes is unknown. To add further clarity to this issue, we performed a comprehensive analysis of behavioral and neurohistological alterations in mice with an allelic series of mutations in the C-terminal end of the Crybb2 gene. Behavioral phenotyping of these three βB2-mutant lines Crybb2O377, Crybb2Philly, and Crybb2Aey2 included assessment of exploratory activity and anxiety-related behavior in the open field, sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle reflex, cognitive performance measured by social discrimination, and spontaneous alternation in the Y-maze. In each mutant line, we also quantified the number of parvalbumin-positive (PV+) GABAergic interneurons in selected brain regions that express CRYBB2. While there were allele-specific differences in individual behaviors and affected brain areas, all three mutant lines exhibited consistent alterations in PPI that paralleled alterations in the PV+ cell number in the thalamic reticular nucleus (TRN). The direction of the PPI change mirrored that of the TRN PV+ cell number thereby suggesting a role for TRN PV+ cell number in modulating PPI. Moreover, as both altered PPI and PV+ cell number are schizophrenia-associated endophenotypes, our result implicates mutated Crybb2 in the development of this neuropsychiatric disorder.
... KANSL1 (8098-fold), CRYBB2 (1688-fold), and PRIMA1 (532-fold) were all highly enriched and have previously been implicated in neurodegeneration. KANSL1 is related to tau expression and CRYBB2 is important in neurodegeneration in the retina of the eye and has been implicated in hippocampal function ( Sun et al., 2013;Zollino et al., 2012). PRIMA1 is important for coordinating acetylcholine receptor subunits in neurons, is important for neuronal outgrowth and is upregulated by MAPK/ERK signaling ( Xie et al., 2009). ...
The mechanisms that lead to neuronal death in neurodegenerative diseases are poorly understood. Prion diseases, like many more common disorders such as Alzheimer's and Parkinson's diseases, are characterized by the progressive accumulation of misfolded disease-specific proteins. The earliest changes observed in brain tissue include a reduction in synaptic number and retraction of dendritic spines, followed by reduced length and branching of neurites. These pathologies are observable during presymptomatic stages of disease and are accompanied by altered expression of transcripts that include miRNAs. Here we report that miR-16 localized within hippocampal CA1 neurons is increased during early prion disease. Modulating miR-16 expression in mature murine hippocampal neurons by expression from a lentivirus, thus mimicking the modest increase seen in vivo, was found to induce neurodegeneration. This was characterized by retraction of neurites and reduced branching. We performed immunoprecipitation of the miR-16 enriched RISC complex, and identified associated transcripts from the co-immunoprecipitated RNA. These transcripts were enriched with predicted binding sites for miR-16, including the validated miR-16 targets APP and BCL2, as well as numerous novel targets. In particular, genes within the neurotrophin receptor mediated MAPK/ERK pathway were potentially regulated by miR-16; including TrkB (NTRK2), MEK1 (MAP2K1) and c-Raf (RAF). Increased miR-16 expression in neurons during presymptomatic prion disease and reduction in proteins involved in MAPK/ERK signaling represents a possible mechanism by which neurite length and branching are decreased during early stages of disease.
... As previously described (Hölter and Glasl, 2011), in the German Mouse Clinic we use a modified version of the social discrimination procedure developed by Engelmann et al. (1995) by using adult ovariectomized 129S1/SvlmJ female mice instead of juveniles as stimulus animals. This procedure has successfully been used to phenotype several mutant mouse lines (Deussing et al., 2010;Pham et al., 2010;Hölter et al., 2013;Sun et al., 2013;Blanco et al., 2014). ...
Genetically modified mouse models have proven useful to study learning and memory processes and the neurocircuitry and molecular mechanisms involved, as well as to develop therapies for diseases involving cognitive impairment. A variety of tests have been developed to measure cognition in mice, and here we present those established and regularly used in the German Mouse Clinic. The test paradigms have been carefully chosen according to reliability of results and disease relevance of the cognitive functions assessed. Further criteria were time efficiency and ease of application. All tests assess slightly different but also overlapping or interacting aspects of learning and memory so that they can be used to complement each other in a comprehensive assessment of cognitive function. The five protocols described are for spontaneous alternation in the Y-maze, social discrimination, object recognition, automated assessment of learning and memory using the IntelliCage, and olfactory discrimination learning. © 2015 by John Wiley & Sons, Inc.
... It is reasonable to expect additional studies on the multifunctional nature of crystallins in a range of processes, including tissue remodeling, inhibition of cell death, regulation of autophagy, and organelle degradation in order to elucidate their "non-crystallin" roles in the lens and nonlens tissues such as the retinal and central nervous system neurons. [280][281][282] The role of Pax6 in regulation of αA-crystallin and βB2-crystallin in neuronal cells 281 suggests that Pax6 regulates crystallin gene expression in retinal ganglion cells and other ocular cells; however, experimental proofs of this concept are still in progress. Studies focused on crystallin gene expression are not only leading models to understand gene regulation in the eye but also more general principles of gene control during embryonic development and organogenesis. ...
The eye and lens represent excellent models to understand embryonic development at cellular and molecular levels. Initial 3D formation of the eye depends on a reciprocal invagination of the lens placode/optic vesicle to form the eye primordium, i.e., the optic cup partially surrounding the lens vesicle. Subsequently, the anterior part of the lens vesicle gives rise to the lens epithelium, while the posterior cells of the lens vesicle differentiate into highly elongated lens fibers. Lens fiber differentiation involves cytoskeletal rearrangements, cellular elongation, accumulation of crystallin proteins, production of extracellular matrix for the lens capsule, and degradation of organelles. This chapter summarizes recent advances in lens development and provides insights into the regulatory mechanisms and differentiation at the level of chromatin structure and dynamics, the emerging field of noncoding RNAs, and novel strategies to fill the gaps in our understanding of lens development.
© 2015 Elsevier Inc. All rights reserved.
... Gene duplications and functional similarities between individual αand β/γ-crystallins, coupled with some very unique roles [e.g. those played by βA3/A1and βB2-crystallins (Sun et al., 2013;Valapala et al., 2014)], impede eye and lens research, as both the serial inactivation of each β/γ-crystallin gene and the generation of a large number of compound mutants are challenging tasks. An alternate approach is to generate largescale deletions in mouse chromosomes 1 and 5 (see A) using a Cre/loxP or a CRISPR-Cas9 system, followed by gene 'rescue' experiments by reintroducing individual and/or combined crystallin gene transgenic units. ...
The ocular lens is a model system for understanding important aspects of embryonic development, such as cell specification and the spatiotemporally controlled formation of a three-dimensional structure. The lens, which is characterized by transparency, refraction and elasticity, is composed of a bulk mass of fiber cells attached to a sheet of lens epithelium. Although lens induction has been studied for over 100 years, recent findings have revealed a myriad of extracellular signaling pathways and gene regulatory networks, integrated and executed by the transcription factor Pax6, that are required for lens formation in vertebrates. This Review summarizes recent progress in the field, emphasizing the interplay between the diverse regulatory mechanisms employed to form lens progenitor and precursor cells and highlighting novel opportunities to fill gaps in our understanding of lens tissue morphogenesis.
© 2014. Published by The Company of Biologists Ltd.
... The most significant association was in CRYBB2 (rs997872, q = 1.75 × 10 −38 ). CRYBB2 encodes βB2-crystallin, which is a structural protein in the ocular lens, 59 but recent studies demonstrated that this gene is expressed in several regions of the mammalian brain 60 and βB2crystallin has a role in hippocampal function and behavioral phenotypes. 59 The second most significant signal was for CHURC1 (churchill domain containing protein 1; rs10131002, q = 1.18 × 10 − 30 ). ...
... CRYBB2 encodes βB2-crystallin, which is a structural protein in the ocular lens, 59 but recent studies demonstrated that this gene is expressed in several regions of the mammalian brain 60 and βB2crystallin has a role in hippocampal function and behavioral phenotypes. 59 The second most significant signal was for CHURC1 (churchill domain containing protein 1; rs10131002, q = 1.18 × 10 − 30 ). A prior study 61 identified CHURC1 as a potential candidate gene for autism. ...
Current catalogs of brain expression quantitative trait loci (eQTL) are incomplete and the findings do not replicate well across studies. All existing cortical eQTL studies are small and emphasize the need for a meta-analysis. We performed a meta-analysis of 424 brain samples across five studies to identify regulatory variants influencing gene expression in human cortex. We identified 3584 genes in autosomes and chromosome X with false discovery rate q<0.05 whose expression was significantly associated with DNA sequence variation. Consistent with previous eQTL studies, local regulatory variants tended to occur symmetrically around transcription start sites and the effect was more evident in studies with large sample sizes. In contrast to random SNPs, we observed that significant eQTLs were more likely to be near 5'-untranslated regions and intersect with regulatory features. Permutation-based enrichment analysis revealed that SNPs associated with schizophrenia and bipolar disorder were enriched among brain eQTLs. Genes with significant eQTL evidence were also strongly associated with diseases from OMIM (Online Mendelian Inheritance in Man) and the NHGRI (National Human Genome Research Institute) genome-wide association study catalog. Surprisingly, we found that a large proportion (28%) of ~1000 autosomal genes encoding proteins needed for mitochondrial structure or function were eQTLs (enrichment P-value=1.3 × 10(-)(9)), suggesting a potential role for common genetic variation influencing the robustness of energy supply in brain and a possible role in the etiology of some psychiatric disorders. These systematically generated eQTL information should be a valuable resource in determining the functional mechanisms of brain gene expression and the underlying biology of associations with psychiatric disorders.
