A. Stoykova - Academia.edu (original) (raw)

Papers by A. Stoykova

The Journal of Neuroscience, 2005

The amygdaloid complex is a group of nuclei that are thought to originate from multiple sites of ... more The amygdaloid complex is a group of nuclei that are thought to originate from multiple sites of the dorsal and ventral telencephalic neuroepithelium. The mechanisms that regulate their development are essentially unknown. We studied the role of Pax6 and Emx2, two transcription factors that regulate regional specification and growth of the telencephalon, in the morphogenesis of the amygdaloid complex. We used a set of specific marker genes that identify distinct amygdaloid nuclei to analyzePax6/Small eyeandEmx2knock-out mutant mouse brains. We found that there is a selective requirement forPax6, but notEmx2, in the formation a subset of nuclei within the amygdaloid complex. Specifically, structures that were not previously considered to be developmentally linked, the nucleus of the lateral olfactory tract and the lateral, basolateral, and basomedial nuclei, all appear to have a common requirement forPax6. Together, our findings provide new insights into the origins and mechanisms un...

Development, 2004

The transcription factor Pax6 plays a key role during development of various organs, including th... more The transcription factor Pax6 plays a key role during development of various organs, including the brain where it affects cell fate, cell proliferation and patterning. To understand how Pax6 coordinates these diverse effects at the molecular level, we examined the role of distinct DNA-binding domains of Pax6, the homeodomain (HD), the paired domain (PD) and its splice variant (5a), using loss- and gain-of-function approaches. Here we show that the PD is necessary for the regulation of neurogenesis, cell proliferation and patterning effects of Pax6, since these aspects are severely affected in the developing forebrain of the Pax6Aey18 mice with a deletion in the PD but intact homeo- and transactivation domains. In contrast, a mutation of the HD lacking DNA-binding (Pax64Neu) resulted in only subtle defects of forebrain development. We further demonstrate distinct roles of the two splice variants of the PD. Retrovirally mediated overexpression of Pax6 containing exon 5a inhibited cell...

The onset of expression of the transcription factor (TF) Nkx2.1 at the ninth embryonic day signal... more The onset of expression of the transcription factor (TF) Nkx2.1 at the ninth embryonic day signals the start of subdivision of the mouse forebrain into its two progenitor zones: the pallium and the subpallium. The pallium being the origin of the cortical excitatory neurons and the subpallium, comprising four progenitor domains: tree ganglionic eminences (GE) known as Lateral, Medial and Caudal GE, respectively (LGE, MGE, CGE) and a small region named the preoptic area, giving rise to almost all cortical and striatal interneurons (IN). MGE, gives rise to 60% of all cortical IN, namely parvalbumin (PV) and somatostatin positive INs, and thus was the first zone we investigated. Of all subpallial progenitor zones the LGE does not contribute to neocortical neurogenesis, but generates neurons only to the olfactory bulb and striatum. Zbtb20 is a zinc finger BTB domain-containing TF related to normal development of the mammalian forebrain with mutant mice having severe defects in the forma...

Science Advances, 2021

H3K9ac promotes basal progenitor amplification, neocortex expansion, and gyrification by activati... more H3K9ac promotes basal progenitor amplification, neocortex expansion, and gyrification by activating Trnp1 expression in evolution.

Cell cycle (Georgetown, Tex.), May 17, 2016

The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) compl... more The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present furthe...

Cell reports, 2015

BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to ... more BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX) and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chrom...

Molecular neurobiology, Aug 8, 2016

The BAF chromatin remodeling complex plays an essential role in brain development. However its fu... more The BAF chromatin remodeling complex plays an essential role in brain development. However its function in postnatal neurogenesis in hippocampus is still unknown. Here, we show that in postnatal dentate gyrus (DG), the BAF170 subunit of the complex is expressed in radial glial-like (RGL) progenitors and in cell types involved in subsequent steps of adult neurogenesis including mature astrocytes. Conditional deletion of BAF170 during cortical late neurogenesis as well as during adult brain neurogenesis depletes the pool of RGL cells in DG, and promotes terminal astrocyte differentiation. These derangements are accompanied by distinct behavioral deficits, as reflected by an impaired accuracy of place responding in the Morris water maze test, during both hidden platform as well as reversal learning. Inducible deletion of BAF170 in DG during adult brain neurogenesis resulted in mild spatial learning deficits, having a more pronounced effect on spatial learning during the reversal test. ...

iScience, Jan 29, 2018

The abundance of basal progenitors (BPs), basal radial glia progenitors (bRGs) and basal intermed... more The abundance of basal progenitors (BPs), basal radial glia progenitors (bRGs) and basal intermediate progenitors (bIPs), in primate brain has been correlated to the high degree of cortical folding. Here we examined the role of BAF155, a subunit of the chromatin remodeling BAF complex, in generation of cortical progenitor heterogeneity. The conditional deletion of BAF155 led to diminished bIP pool and increased number of bRGs, due to delamination of apical RGs. We found that BAF155 is required for normal activity of neurogenic transcription factor PAX6, thus controlling the expression of genes that are involved in bIP specification, cell-cell interaction, and establishment of adherens junction. In a PAX6-dependent manner, BAF155 regulates the expression of the CDC42 effector protein CEP4, thereby controlling progenitor delamination. Furthermore, BAF155-dependent chromatin remodeling seems to exert a specific role in the genesis of BPs through the regulation of human RG-specific gene...

Experimental Cell Research, 1998

We have used different gene trap vectors and in vitro preselection of embryonic stem (ES) cells f... more We have used different gene trap vectors and in vitro preselection of embryonic stem (ES) cells for a large scale screening of insertional mutations in developmentally regulated genes. A gene trap vector was constructed, which contains an internal ribosome entry site (IRES) upstream from a ␤geo selectable-reporter fusion gene. Analysis of 801 independent integrations revealed that the IRES␤geo vector allows for a global enrichment of about 15 folds in the number of detectable gene trap events when compared with a conventional ␤geo vector. Characterization of in vitro and in vivo lacZ expression suggested that this IRES-based vector is able to capture a wide range of genes expressed in a variety of tissues and developmental stages, and it can also allow trapping of genes expressed at very low levels in ES cells. A preselection protocol was devised, where gene-trapped ES cells were grown in the presence of specific growth/differentiation factors such as follistatin, nerve growth factor, and retinoic acid. Several gene trap integrations were found to be either activated or repressed by one of these factors. Characterization of lacZ expression during embryogenesis showed a strong enrichment of restricted patterns in vivo after ES cell preselection. These results suggest that a combination of IRES␤geo vector and in vitro preselection is more effective for the capture and mutation of a large number of developmental genes.

Behavioural Pharmacology, 2005

Molecular brain, 2016

During corticogenesis, genetic programs encoded in progenitor cells at different developmental st... more During corticogenesis, genetic programs encoded in progenitor cells at different developmental stages and inherited in postmitotic neurons specify distinct layer and area identities. Transcription factor Zbtb20 has been shown to play a role for hippocampal development but whether it is implicated in mammalian neocortical morphogenesis remains unknown. Here, we report that during embyogenesis transcription factor Zbtb20 has a dynamic spatio-temporal expression pattern in mitotic cortical progenitors through which it modulates the sequential generation of cortical neuronal layer identities. Zbtb20 knock out mice exhibited enhanced populations of early born L6-L4 neuronal subtypes and a dramatic reduction of the late born L3/L2 neurons. This defect was due to a temporal misbalance in the production of earlier versus later born neurons, leading to a progressive diminishing of the progenitor pool for the generation of L3-L2 neurons. Zbtb20 implements these temporal effects in part by bin...

Nature Neuroscience, 2007

The amygdaloid complex consists of diverse nuclei that belong to distinct functional systems, yet... more The amygdaloid complex consists of diverse nuclei that belong to distinct functional systems, yet many issues about its development are poorly understood. Here, we identify a stream of migrating cells that form specific amygdaloid nuclei in mice. In utero electroporation showed that this caudal amygdaloid stream (CAS) originated in a unique domain at the caudal telencephalic pole that is contiguous with the dorsal pallium, which was previously thought to generate only neocortical cells. The CAS and the neocortex share mechanisms for specification (transcription factors Tbr1, Lhx2 and Emx1/2) and migration (reelin and Cdk5). Reelin, a critical cue for migration in the neocortex, and Cdk5, which is specifically required for migration along radial glia in the neocortex, were both selectively required for the normal migration of the CAS, but not for that of other amygdaloid nuclei. This is first evidence of a dorsal pallial contribution to the amygdala, demonstrating a developmental and mechanistic link between the amygdala and the neocortex.

Nature Neuroscience, 2002

The molecular mechanisms that trigger morphogenesis of cerebral cortex instead of adjacent telenc... more The molecular mechanisms that trigger morphogenesis of cerebral cortex instead of adjacent telencephalic structures, such as basal ganglia and fimbria, are still largely unknown. Several transcription factor genes differentially expressed in the early telencephalic wall may be crucial for its later morphological subdivision into cerebral cortex and adjacent structures; recent experimental work on mutant mice has confirmed these predictions. The selector genes that activate corticogenesis in place of other competing processes, however, have not been identified. The restriction of homeobox gene Lhx2 products to the cortical anlage sets up the boundary between presumptive cortex and cortical hem, namely the forerunner of the fimbria 1,2. The confinement of homeobox gene Gsh2 products to basal forebrain fixes the boundary between pallial and striatal fields 3,4. However, cortical specification is not fully abolished in Lhx2-/mutants and complete striatal-cortical conversion does not occur in Gsh2 knockouts 1-4. The bHLH genes Ngn1/Ngn2 and Mash1 promote multiple aspects of corticogenesis and basal ganglia morphogenesis respectively, although they do not act as 'master genes'. Rather, they simply link regional patterning to the activation of specific neuronogenetic pathways in these structures 5. The zinc-finger gene Gli3 is also crucial for corticogenesis; but the cortex of Gli3-/mutants, ventralized and reduced in size, still retains signs of cortical specification 6,7. The two homeobox genes Emx2 and Pax6, which are expressed in the dorsal telencephalic wall from early in development 8-10 , are involved in multiple aspects of cortical morphogenesis including neuroblast proliferation 10-12 , development of radial glia 10,13 , neuronal radial migration and lamination 13-15 , regionalization and arealization 11,16,17 and histogenesis of archicortex and lateral cortex 11,18-21. Nevertheless, in the absence of either Emx2 or Pax6, cerebral cortex forms and, even if variously affected, is

Developmental Biology, 2005

Development, 2001

The cerebral cortex is composed of a large variety of different neuron types. All cortical neuron... more The cerebral cortex is composed of a large variety of different neuron types. All cortical neurons, except some interneurons, are born in two proliferative zones, the cortical ventricular (VZ) and subventricular (SVZ) zones. The relative contribution of both proliferative zones to the generation of the diversity of the cortical neurons is not well understood. To further dissect the underlying mechanism, molecular markers specific for the SVZ are required. Towards this end we performed a subtraction of cDNA libraries, generated from E15.5 and E18.5 mouse cerebral cortex. A novel cDNA, Svet1, was cloned which was specifically expressed in the proliferating cells of the SVZ but not the VZ. The VZ is marked by the expression of the Otx1 gene. Later in development, Svet1 and Otx1 were expressed in subsets of cells of upper (II-IV) and deep (V-VI) layers, respectively. In the reeler cortex, where the layers are inverted, Svet1 and Otx1 label precursors of the upper and deeper layers, resp...

Mutations in the gene for the transcription factor, Pax6, induce marked developmental abnormaliti... more Mutations in the gene for the transcription factor, Pax6, induce marked developmental abnormalities in the CNS and the eye, but the cellular mechanisms that underlie the phenotype are unknown. We have examined the adhesive properties of cells from the developing forebrain in Small eye, the Pax6 mutant mouse. We have found that the segregation normally observed in aggregates of cortical and striatal cells in an in vitro assay is lost in Small eye. This correlates with an alteration of in vivo expression of the homophilic adhesion molecule, R-cadherin. Moreover, the boundary between cortical and striatal regions of the telencephalon is dramatically altered in Small eye: radial glial fascicles do not form at the border, and the normal expression of R-cadherin and tenascin-C at the border is lost. These data suggest a link between the transcription factor, Pax6, R-cadherin expression, cellular adhesion and boundary formation between developing forebrain regions.

Glial-Neuronal Communication in Development and Regeneration, 1987

Neural Cell Specification, 1995