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PubMed2025

Single-cell-scale spatial transcriptome of the developing and adult mouse ovary.

Mammalian ovary development is essential for female fertility, involving the complex spatial patterning of diverse cell types to establish the finite reserve of ovarian follicles. While single-cell transcriptome analyses have provided important insights into the mechanisms driving specification and developmental trajectories of ovarian cells, they disrupt this crucial spatial context. To overcome this limitation, we used 10X Genomics Visium HD spatial transcriptomics to analyze the developing mouse ovary while maintaining its native cellular architecture. We captured all ovarian cell types at eight key fetal and postnatal timepoints, generating a near single cell resolution library of spatial gene expression across ovarian development. This comprehensive dataset allows analysis of dynamic transcriptional signatures associated with unique spatial patterning throughout development, including the establishment of cortex and medulla and assembly of ovarian follicles in each region. This dataset represents a fundamental resource for the investigation of regulatory mechanisms driving spatial patterning of the ovary and opens new avenues to explore the spatial determinants of female fertility and reproductive longevity.

Journal Article↗
PubMed1996

Binary expression of olfactory bulb-protein tyrosine phosphatase in rat central nervous system: developmental gene regulation in neonate cerebral cortex and constitutive expression in olfactory-rhinencephalon.

Olfactory bulb-protein tyrosine phosphatase (OB-PTP) is a receptor type PTPase dominantly expressed in olfactory bulb. Previously, we isolated and molecularly cloned a rat OB-PTP cDNA from an embryonal brain cDNA library. In the present study, we investigated its temporal and spatial gene expression by Northern blot and in situ hybridization analysis. The expression of OB-PTP gene was firstly detected in day 16 post coitum embryo and significantly increased during the late-gestational stage, attaining the highest level in the first week of neonate. The OB-PTP transcript was then down-regulated postnatally and was detected barely in an adult brain. In situ hybridization analysis showed that the transcript was characteristically localized in the postmitotic neurons of cerebral cortex and subcortical structures, and was down-regulated by day 28 when the cortical and subcortical structures have been organized. In the olfactory-rhinencephalon system including olfactory bulb and piriform cortex, the OB-PTP was preferentially expressed in the postmitotic neurons, and in contrast continuously expressed in the matured brain. Based on the evidence that DPTP10D, the Drosophila homolog of OB-PTP, is localized in the axons of specific pioneer neurons in Drosophila embryo, the OB-PTP is presumably involved in the axonogenesis of cortical and subcortical neurons as well as olfactory neurons in mammalian central nervous system. The biological significance of transcriptional regulation in olfactory system is discussed in terms of continuous axonal connections by regenerating olfactory neurons.

Animals↗
PubMed2001

Microarray-based analysis of early development in Xenopus laevis.

In order to examine transcriptional regulation globally, during early vertebrate embryonic development, we have prepared Xenopus laevis cDNA microarrays. These prototype embryonic arrays contain 864 sequenced gastrula cDNA. In order to analyze and store array data, a microarray analysis pipeline was developed and integrated with sequence analysis and annotation tools. In three independent experimental settings, we demonstrate the power of these global approaches and provide optimized protocols for their application to molecular embryology. In the first set, by comparing maternal versus zygotic transcription, we document groups of genes that are temporally regulated. This analytical approach resulted in the discovery of novel temporally regulated genes. In the second, we examine changes in gene expression spatially during development by comparing dorsal and ventral mesoderm dissected from early gastrula embryos. We have discovered novel genes with spatial enrichment from these experiments. Finally, we use the prototype microarray to examine transcriptional responses from embryonic explants treated with activin. We selected genes (two of which are novel) regulated by activin for further characterization. All results obtained by the arrays were independently tested by RT-PCR or by in situ hybridization to provide a direct assessment of the accuracy and reproducibility of these approaches in the context of molecular embryology.

Animals↗
PubMed1997

Developmental expression of morphoregulatory genes in the mouse embryo: an analytical approach using a novel technology.

The molecular techniques of in situ transcription and antisense RNA amplification (IST/aRNA) have allowed for the monitoring of coordinate changes in the expression of multiple genes simultaneously. However, the analysis of their concurrent behavior during murine embryogenesis has been problematic. Studies involving the investigation of temporal and spatial gene expression during embryogenesis have focused solely on the analysis of isolated, single gene events. Such an approach has failed to provide an integrative picture of genetic control over the varied and complicated cellular processes governing embryogenesis. In order to interpret the enormous amount of gene expression data generated by these procedures, we have attempted to develop an analytical framework by employing the statistical concepts of principal components analysis (PCA). For the current study, we performed IST/aRNA on neural tubes dissected from the highly inbred LM/Bc murine strain collected during four gestational time periods. A subset of these genes, representing a partial signaling pathway in the developing neuroepithelium, was then subjected to PCA. Here, we report that PCA highlighted the transcriptional interplay among the genes p53, wee-1, Tgf beta-2, and bcl-2 such that the combined reciprocal regulation of their gene products is suggestive of a predominant proliferative state for the developing neuroepithelium. The application of PCA to the gene expression data has elucidated previously unknown interrelationships among cell cycle genes, growth, and transcription factors on a transcriptional level during critical stages of neurulation. The information gleaned from this analysis, while not definitive, suggests distinct hypotheses to guide future research.

Analysis of Variance↗
PubMed1997

Tissue-specific and developmental regulation of the rat insulin II gene enhancer, RIPE3, in transgenic mice.

The rat insulin II gene enhancer, RIPE3 (-126 to -86), mediates beta-islet cell-specific activity in transfection assays. To investigate the in vivo activity of RIPE3, we generated mice carrying a transgene consisting of three copies of RIPE3 linked to a minimal chicken ovalbumin promoter in conjunction with sequences encoding the human growth hormone gene. 13 transgenic mice were obtained, 11 of which expressed the transgene, as determined by serum radioimmunoassay for human growth hormone. Expression of the transgene was assessed for cell specificity by immunocytochemistry. The pancreatic islet cells invariably stained for growth hormone, while the acinar and ductal cells did not. Staining of adjacent sections for insulin, glucagon, and somatostatin revealed that growth hormone was expressed in the beta-cell in all of the mice analyzed, but in some mice alpha-cells also contained growth hormone. RNase protection analysis revealed that the tissues that consistently express the transgene in these animals are the pancreas and brain. Developmental analysis revealed that the transgene was expressed in the pancreatic bud at embryonic day 9.5, corresponding to the temporal expression pattern of the insulin gene. These results signify that an element as small as 41 base pairs is capable of regulating pancreatic temporal and spatial gene expression in vivo.

Animals↗
PubMed2026

CAGNet: a structure-aware clustering-alternated graph network for cell-cell interaction inference in spatial transcriptomics.

MOTIVATION: Understanding cell-cell interactions (CCIs) in spatial transcriptomics is crucial for uncovering the spatial organization and functional heterogeneity of tissues. However, existing graph-based models typically rely on static clustering or fixed adjacency structures, which limits their ability to capture dynamic cellular relationships. RESULTS: We propose CAGNet, a two-stage framework for CCI inference from spatial transcriptomics data. In Stage 1, a Graph Attention Network encoder with joint feature and graph reconstruction learns structure-aware node embeddings from spatial gene expression profiles. In Stage 2, an alternating optimization mechanism iteratively updates cluster centers via KL-guided soft assignment and refines node embeddings through spatial graph reconstruction, establishing a closed-loop between representation learning and clustering. Experiments on three 10x Genomics Visium datasets demonstrate that CAGNet consistently outperforms six CCI inference baselines across ACC, AUC, AP, Precision, Recall, and F1. CAGNet also achieves the highest Adjusted Rand Index on all three datasets against six spatial domain identification methods, confirming that the learned embeddings capture biologically relevant spatial organization. Information-theoretic analysis further shows that CAGNet retains the highest mutual information between input features and learned embeddings among all compared methods. Ablation studies and 5-fold cross-validation confirm the contribution of each component and the reproducibility of the results. AVAILABILITY: The proposed method is implemented in the CAGNet package available at http://github.com/mahan1233333-maker/CAGNet .

Spatial Transcriptomics↗
PubMed1997

Kainate-evoked modulation of gene expression in rat brain.

Kainate is a glutamate analog that produces neuronal excitation resulting in seizures within hours following its intraperitoneal injection into adult rats. Then, at 2-3 days after the treatment, neurodegeneration of apoptotic character can be observed in limbic system. As a consequence, plastic reorganization and glial reactivation phenomena occur. These physiological and pathological responses are reflected by specific changes in gene expression, that can be dissected according to their spatio-temporal patterns. The early phase of gene expression observed in all hippocampal subfields appears to reflect a sudden burst of spiking activity. Changes in mRNA levels restricted to dentate gyrus are suggestive of a link to neuronal plasticity. The late gene expression response implies its correlation either to neuronal cell death or glial reactivation, depending on cellular localization of gene products. Thus analysis of the temporal and spatial gene expression pattern in the hippocampus after kainate treatment may provide clues revealing specific phenomena to which gene expression could be attributed.

Animals↗
PubMed1992

Spatial and temporal gene expression patterns occur during corm development.

We investigated gene expression patterns that occur during taro corm development. Two-dimensional gel electrophoresis identified several different prevalent proteins that accumulate during corm development. Microsequencing studies indicated that some of these proteins are related to taste-modifying proteins, such as curculin and miraculin, and proteins found in other storage organs, such as sporamin and the Kunitz trypsin inhibitor. A curculin-encoding cDNA clone, designated as TC1, was identified that corresponds to a highly prevalent 1-kb corm mRNA. The TC1 mRNA accumulates during corm development, is more prevalent in corm apical than basal regions, and is either absent, or present at low concentrations, in other vegetative organs such as the leaf and root. In situ hybridization experiments showed that the TC1 mRNA is highly concentrated in corm storage parenchyma cells and is absent, or present in reduced concentrations, in other corm cells and tissues. Our results show that corm development is associated with the differentiation of specialized cells and tissues, and that these differentiation events are coupled with the temporal and spatial expression of corm-specific genes.

Amino Acid Sequence↗
PubMed2016

Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

Atlases as Topic↗
PubMed2006

EMAGE: a spatial database of gene expression patterns during mouse embryo development.

EMAGE (http://genex.hgu.mrc.ac.uk/Emage/database) is a freely available, curated database of gene expression patterns generated by in situ techniques in the developing mouse embryo. It is unique in that it contains standardized spatial representations of the sites of gene expression for each gene, denoted against a set of virtual reference embryo models. As such, the data can be interrogated in a novel and abstract manner by using space to define a query. Accompanying the spatial representations of gene expression patterns are text descriptions of the sites of expression, which also allows searching of the data by more conventional text-based methods.

Animals↗
PubMed1993

Major temporal and spatial patterns of gene expression during differentiation of the sea urchin embryo.

We have investigated the temporal and spatial patterns of accumulation of mRNAs randomly selected from the sea urchin gastrula polyadenylated RNA population. Three different assays show that the predominant temporal pattern of expression, exhibited by about three-fourths of these messages, consists of a large (mean 80-fold) increase in mRNA abundance between egg and gastrula stages. Most mRNAs are present in the maternal population and are detectable on blots as single mature-sized messages; however, a large number of high-molecular-weight, heterodisperse transcripts containing these same sequences also exist in the egg cytoplasm. The majority of gastrula messages are not embryo specific but are present in total adult urchin RNA at concentrations similar to those in embryos. Fine-scale RNA blot analysis indicates that the majority of mRNAs begin to accumulate at very early blastula stages, although there is considerable diversity in the time when these messages reach peak abundance. Most gastrula mRNAs are also spatially regulated during development. The observed distributions can be categorized into three major functional or regulatory classes: (1) Forty percent of mRNAs accumulate in cells which are cycling or preparing for growth. (2) About one-third of the messages accumulate in one or more differentiating cell types. (3) Only slightly more than one-fourth of the messages are present in all cell types throughout development. Most tissue-specific messages are relatively abundant, indicating that the differentiated functions of cells are executed through mRNAs operating at the level of hundreds of copies per cell. In contrast, most rare messages are expressed in most or all cell types, in which they function at only a few copies per cell. All messages which begin to accumulate before hatching blastula stage are initially distributed broadly, and their distribution becomes progressively restricted during embryogenesis. In contrast, all messages which begin to accumulate after the onset of gastrulation accumulate only in discrete subsets of cells. The results presented here illustrate much more extensive temporal regulation of gene expression during sea urchin embryogenesis than previously detected. This is accompanied by spatial regulation of expression of most genes which is itself temporally modulated as the cellular requirements for cell division and differentiation change during development.

Age Factors↗
PubMed1995

Nuclear translocation of a maternal CCAAT factor at the start of gastrulation activates Xenopus GATA-2 transcription.

The transcription factor GATA-2 is present in blood cell precursors and plays a pivotal role in the control of erythroid differentiation. In Xenopus embryos, low levels of GATA-2 mRNA are maternally derived, while the onset of zygotic GATA-2 expression coincides with commitment to haematopoietic lineages. However, its initial transcriptional activation is not restricted to the presumptive blood islands, but occurs throughout ventral and lateral regions, in all three germ layers. In order to determine how this expression pattern is controlled, we have isolated and characterized the Xenopus GATA-2 gene. We show that 1.65 kb of 5' flanking sequences are sufficient to direct both correct transcriptional initiation in oocytes and appropriate temporal and spatial gene expression in early embryos. The transgene is activated during gastrulation and by neurula stages in predominantly expressed in the ventral hemisphere. We demonstrate that a CCAAT element is necessary for gene activity in both systems and that extracts prepared from oocytes and embryos contain a factor which specifically recognizes this element. We also show that cytoplasmic localization inhibits the function of this CCAAT factor until the beginning of gastrulation, when the zygotic GATA-2 gene is activated. These observations extend our understanding of the mechanisms by which maternal factors control the temporal activation of transcription in early vertebrate embryos.

Alternative Splicing↗
PubMed2001

Development of a two-part transcription probe to determine the completeness of temporal and spatial compartmentalization of gene expression during bacterial development.

We have developed a two-part test, using the Bacillus subtilis sacB/SacY transcription antitermination system, to evaluate the completeness of temporal and spatial compartmentalization of gene expression during bacterial cell development. Transcription of sacY(1-55) (encoding a constitutively active form of the antiterminator, SacY) is directed by one promoter, whereas transcription of sacB'-'lacZ (the target of SacY action) is directed by the same or another promoter. To obtain beta-galactosidase activity, SacY(1-55) needs to be present when sacB'-'lacZ is being transcribed. We tested the system by analyzing the spatial compartmentalization of the activities of RNA polymerase final sigma factors, which are tightly regulated during sporulation of B. subtilis: final sigma(F) and then final sigma(G) in the prespore, final sigma(E) and then final sigma(K) in the mother cell. We have confirmed that the activities of final sigma(F) and final sigma(E) are spatially compartmentalized. We have demonstrated that there is also sharp temporal compartmentalization, with little or no overlap in the activities of final sigma(F) and final sigma(G) or of final sigma(E) and final sigma(K). In contrast, we found no compartmentalization of the activity of the main vegetative factor, final sigma(A), which continued to be active alongside all of the sporulation-specific final sigma factors. We also found no temporal compartmentalization of expression of loci that are activated during the development of competent cells of B. subtilis, a developmental program distinct from spore formation. A possible mechanism to explain the temporal compartmentalization of final sigma(F) and final sigma(G) activities is that the anti-sigma factor SpoIIAB transfers from final sigma(G) to final sigma(F).

Bacillus subtilis↗
PubMed2004

Gene silencing using a heat-inducible RNAi system in Arabidopsis.

Controlling gene expression during plant development is an efficient tool to explore gene function. In this paper, we describe a gene expression system driven by a heat-shock gene promoter (HSP18.2), to trigger the expression of an intron-containing inverted-repeat. RNA interference became a powerful way for gene functional analysis by reverse genetic approaches. However, constitutive gene silencing cannot be used with genes involved in fundamental processes such as embryo viability. Inducible promoters provide an alternative approach for temporal and spatial gene expression control and we described here a new system, complementary to those using chemical gene inducers. To evaluate the efficiency of this system, RNA corresponding to the phytoene desaturase gene of Arabidopsis thaliana was used as a reporter gene in transgenic plants and a comparative study was performed using either the CaMV35S constitutive promoter or the HSP18.2 inducible promoter.

Arabidopsis↗
PubMed1994

An analysis of Xenopus tyrosine kinase genes and their expression in early development.

Xenopus laevis and X. borealis were screened for tyrosine kinase genes using the polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR and 34 X. laevis and 23 X. borealis tyrosine genes were identified. Eighteen of the genes represented novel tyrosine kinase family members. The rest could be classified into known tyrosine kinase subfamilies, of which however only three have been previously identified in Xenopus. Eight clones, including bFGFR (xFGFR1) and potential Trk, Ins R., Fak, Fyn, and Abl homologs, were used to probe temporal and spatial gene expression in early development. Quantitative RT-PCR and whole-mount and in situ hybridization showed that most of these mRNAs were present throughout development and were broadly distributed, mainly in ectodermal and mesodermal derived tissues. At the blastula stage, bFGFR mRNA was detected within the ectoderm and a gradient of expression was noted within the invaginating mesoderm. The unexpected promiscuous expression of many tyrosine kinase genes in early development is discussed.

Amino Acid Sequence↗
PubMed1996

Spatial and temporal distribution of lamprin mRNA during chondrogenesis of trabecular cartilage in the sea lamprey.

The temporal and spatial expression patterns of lamprin, the principle structural protein in lamprey cartilages, were examined by in situ hybridization during chondrogenesis of trabecular cartilage in day 17-33 post-fertilization prolarval lampreys. Lamprin mRNA transcripts were first detected during day 19, concomitant with the end of the condensation phase of chondrogenesis and the initiation of matrix synthesis as indicated by light microscopic examination. In the stages which followed, the hybridization signal increased with progressive intensity, paralleling matrix synthesis, suggesting transcriptional control of lamprin gene expression. Spatially, lamprin expression patterns mirrored the rostrocaudal development of the trabecular cartilage rudiment. No signal was detected over adjacent tissues or control sections. Some similarities exist between the temporal patterns of lamprin expression and the expression of matrix proteins such as elastin and collagen of higher vertebrates. It is concluded that certain aspects of chondrogenesis are critical to the normal development of a functional cartilaginous matrix and are conserved throughout the vertebrate taxa.

Animals↗
PubMed1994

5' flanking region of the Clara cell secretory protein gene specifies a unique temporal and spatial pattern of gene expression in the developing pulmonary epithelium.

Expression of a transgene containing 2.25 kb of the 5' flanking region of the rat Clara cell secretory protein gene and the human growth hormone gene was examined in developing mice. Despite an absolute preservation of tissue specificity based on RNA blot analysis, transgene-specific transcripts were detectable as early as 12.5 days of gestation, at least 4 days prior to endogenous Clara cell secretory protein gene expression. As differentiation proceeded, in situ hybridization revealed an increasingly restricted pattern of transgene expression in the developing pulmonary epithelium, such that by day 16.5 of gestation endogenous and transgene expression were confined to identical cells within the bronchiolar epithelium. The temporal discordance in transgene expression suggests the presence of unique cis-acting elements within the Clara cell secretory protein gene, not present in the transgene, which transduce developmental timing within pulmonary epithelium by actively repressing Clara cell secretory protein gene expression during early development. The unique expression of this transgene serves as a lineage marker in the respiratory epithelium and unmasks a temporal and spatial pattern of gene expression not observed in any pulmonary genes.

Animals↗
PubMed2004

Adenovirus vectors targeting alphaV integrin or heparan sulfate receptors display different distribution of transgene activity after intramuscular injection.

BACKGROUND: Modification of the fiber proteins in replication-deficient adenoviral (Ad) vectors through incorporation of specific receptor-binding motifs may represent a strategy to enhance their tissue targeting capabilities. METHODS: In this study, we compared an unmodified Ad (GV10) with two mutated vectors obtained by insertion of specific target sequences that redirect binding, either toward alpha(V) integrin (RGD) or heparan sulfate (UTV) cellular receptors, for reporter gene expression spatial distribution in the rabbit skeletal muscle. In a first series of experiments, injection volume was kept constant and activity of a lacZ transgene was evaluated 48 h after injection of the Ad vectors at different doses. In separate experiments, the effects of different volumes of injection at a constant dose of Ad vector were monitored. RESULTS: All vectors evaluated showed a significant increase in the number of lacZ-positive muscle segments, with increasing vector dose. However, in muscles treated with the UTV vector, fewer muscle fibers were beta-gal-positive than in GV10 or RGD vector treated animals. In fact, total beta-gal activity increased in a dose-dependent fashion in the GV10- and RGD-treated muscles, but not in the UTV-treated ones. Remarkably, in samples from UTV-treated animals, a volume-dependent enhancement of transgene expression was observed during experiments performed at the same dose and different injection volumes. CONCLUSIONS: The results of the present study demonstrate that altering Ad affinity for cellular receptors modulates the level and distribution of transgene activity, conferring characteristics that may allow for treatment customization.

Adenoviridae↗