LHX2 regulates dendritic morphogenesis in layer II/III of the neocortex via distinct pathways in progenitors and postmitotic neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1067660 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27684022_1.fastq.gz | Fastqsanger.gz | |||
| SRR27684022_2.fastq.gz | Fastqsanger.gz | |||
| SRR27684023_1.fastq.gz | Fastqsanger.gz | |||
| SRR27684023_2.fastq.gz | Fastqsanger.gz | |||
| SRR27684024_1.fastq.gz | Fastqsanger.gz |
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Project description:In the mammalian neocortex, excitatory neurons that send projections via the corpus callosum are critical to integrating information across the two brain hemispheres. The molecular mechanisms governing the development of the dendritic arbours and spines of these callosal neurons are poorly understood, yet these features are critical to their physiological properties. LIM Homeodomain 2 (Lhx2), a regulator of fundamental processes in cortical development, is expressed in postmitotic callosal neurons occupying layer II/III of the neocortex and also in their progenitors in the embryonic day (E) 15.5 ventricular zone of the mouse neocortex. We tested whether this factor is essential for dendritic arbour configuration and spine morphogenesis of layer II/III neurons. Here, we report loss of Lhx2 either in postmitotic callosal neurons or their progenitors, resulting in shrunken dendritic arbours and perturbed spine morphology. In postmitotic neurons, we identified that LHX2 regulates dendritic and spine morphogenesis via the canonical Wnt/β Catenin signalling pathway. Constitutive activation of this pathway in postmitotic neurons recapitulates the Lhx2 loss-of-function phenotype. In E15.5 progenitors, we identified that bHLH transcription factor Neurog2 mediates LHX2 function in regulating dendritic and spine morphogenesis. We show that Neurog2 expression increases upon loss of Lhx2 and that shRNA-mediated Neurog2 knockdown rescues the loss of Lhx2 phenotype. Our study uncovers novel LHX2 functions consistent with its temporally dynamic and multifunctional roles in the cortical circuit assembly.
2025-05-25 | GSE253914 | GEO
Project description:Current knowledge suggests that cortical sensory area identity is controlled by transcription factors (TFs) that specify area features in progenitor cells and subsequently their progeny in a one-step process. However, how neurons acquire and maintain these features is unclear. We have used conditional inactivation restricted to postmitotic cortical neurons in mice to investigate the role of the TF LIM homeobox 2 (Lhx2) in this process and report that in conditional mutant cortices area patterning is normal in progenitors but strongly affected in cortical plate (CP) neurons. We show that Lhx2 controls neocortical area patterning by regulating downstream genetic and epigenetic regulators that drive the acquisition of molecular properties in CP neurons. Our results question a strict hierarchy in which progenitors dominate area identity, suggesting a novel and more comprehensive two-step model of area patterning: In progenitors, patterning TFs prespecify sensory area blueprints. Sequentially, sustained function of alignment TFs, including Lhx2, is essential to maintain and to translate the blueprints into functional sensory area properties in cortical neurons postmitotically. Our results reemphasize critical roles for Lhx2 that acts as one of the terminal selector genes in controlling principal properties of neurons.
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Project description:Eye formation is regulated by a complex network of eye field transcription factors (EFTFs), including LIM-homeodomain gene LHX2. We disrupted LHX2 function at different stages during this process using a conditional knock-out strategy in mice. We find that LHX2 function is required in an ongoing fashion to maintain optic identity across multiple stages, from the formation of the optic vesicle to the differentiation of the neuroretina. At each stage, loss of Lhx2 led to upregulation of a set of molecular markers that are normally expressed in the thalamic eminence and in the anterodorsal hypothalamus in a portion of the optic vesicle or retina. Furthermore, the longer LHX2 function was maintained, the further optic morphogenesis progressed. Early loss of function caused profound mispatterning of the entire telencephalic-optic-hypothalamic field, such that the optic vesicle became mispositioned and appeared to arise from the diencephalic-telencephalic boundary. At subsequent stages, loss of Lhx2 did not affect optic vesicle position but caused arrest of optic cup formation. If Lhx2 was selectively disrupted in the neuroretina from E11.5, the neuroretina showed gross dysmorphology along with aberrant expression of markers specific to the thalamic eminence and anterodorsal hypothalamus. Our findings indicate a continual requirement for LHX2 throughout the early stages of optic development, not only to maintain optic identity by suppressing alternative fates but also to mediate multiple steps of optic morphogenesis. These findings provide new insight into the anophthalmic phenotype of the Lhx2 mutant and reveal novel roles for this transcription factor in eye development.
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Project description:The Lhx2 transcription factor plays essential roles in morphogenesis and patterning of ectodermal derivatives, as well as in controlling stem cell activity. Lhx2 is expressed in the hair follicle (HF) buds, while in postnatal telogen HFs Lhx2+ cells reside in the stem cell-enriched epithelial compartments (bulge, secondary hair germ) and co-express selected stem cell markers (Sox9, Tcf4 and Lgr5). Lhx2+ cells represent the vast majority of cells in the bulge and secondary hair germ that proliferate in response to skin injury. This is functionally important, since the wound re-epithelialization is significantly retarded in heterozygous Lhx2 knockout (+/-) mice, while anagen onset in the HFs located closely to the wound is accelerated compared to wild-type mice. Cell proliferation in the bulge and the number of Sox9+ and Tcf4+ cells in the HFs closely adjacent to the wound in Lhx2+/- mice are decreased in comparison to wild-type controls, while expression of Lgr5 and cell proliferation in the secondary hair germ are increased. Furthermore, acceleration of wound-induced anagen development in Lhx2+/- mice is inhibited by administration of Lgr5 siRNA. In addition, Chip-on-chip/ChIP-qPCR and reporter assay analyses reveal Sox9, Tcf4 and Lgr5 as direct Lhx2 targets in keratinocytes. These data strongly suggest that Lhx2 positively regulates Sox9 and Tcf4 in the bulge cells and promotes wound re-epithelization, while it simultaneously negatively regulates Lgr5 in the secondary hair germ and inhibits HF cycling. Thus, Lhx2 operates as a regulator of epithelial stem cell activity during skin response to injury. Chromatin form primary mouse keratinocytes (PMK) was subjected to ChIP analysis with Lhx2 antibody; input and ChIP DNA were labelled with Cy3 and Cy5 respectivly and used form Nimblegen MM8 Mouse Promoter Array
2011-10-03 | E-GEOD-32514 | biostudies-arrayexpress
Project description:The Lhx2 transcription factor plays essential roles in morphogenesis and patterning of ectodermal derivatives, as well as in controlling stem cell activity. Lhx2 is expressed in the hair follicle (HF) buds, while in postnatal telogen HFs Lhx2+ cells reside in the stem cell-enriched epithelial compartments (bulge, secondary hair germ) and co-express selected stem cell markers (Sox9, Tcf4 and Lgr5). Lhx2+ cells represent the vast majority of cells in the bulge and secondary hair germ that proliferate in response to skin injury. This is functionally important, since the wound re-epithelialization is significantly retarded in heterozygous Lhx2 knockout (+/-) mice, while anagen onset in the HFs located closely to the wound is accelerated compared to wild-type mice. Cell proliferation in the bulge and the number of Sox9+ and Tcf4+ cells in the HFs closely adjacent to the wound in Lhx2+/- mice are decreased in comparison to wild-type controls, while expression of Lgr5 and cell proliferation in the secondary hair germ are increased. Furthermore, acceleration of wound-induced anagen development in Lhx2+/- mice is inhibited by administration of Lgr5 siRNA. In addition, Chip-on-chip/ChIP-qPCR and reporter assay analyses reveal Sox9, Tcf4 and Lgr5 as direct Lhx2 targets in keratinocytes. These data strongly suggest that Lhx2 positively regulates Sox9 and Tcf4 in the bulge cells and promotes wound re-epithelization, while it simultaneously negatively regulates Lgr5 in the secondary hair germ and inhibits HF cycling. Thus, Lhx2 operates as a regulator of epithelial stem cell activity during skin response to injury.
2011-10-04 | GSE32514 | GEO
Project description:Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that Tbr1, a transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. Tbr1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in Tbr1 mutants. Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. Tbr1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, Tbr1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons. Mouse E14.5 neocortices and Postnatal day (P) 0.5 brains: E14.5 neocortices KO, 3; E14.5 neocortices WT, 3; Postnatal day (P) 0.5 brains frontal WT, 4; Postnatal day (P) 0.5 brains frontal KO, 4; Postnatal day (P) 0.5 brains parietal WT, 4; Postnatal day (P) 0.5 brains parietal KO, 4; Postnatal day (P) 0.5 brains occipital WT, 4; Postnatal day (P) 0.5 brains occipital KO, 4.
2010-07-27 | E-GEOD-22371 | biostudies-arrayexpress
Project description:The Lhx2 transcription factor plays essential roles in morphogenesis and patterning of ectodermal derivatives, as well as in controlling stem cell activity. Lhx2 is expressed in the hair follicle (HF) buds, while in postnatal telogen HFs Lhx2+ cells reside in the stem cell-enriched epithelial compartments (bulge, secondary hair germ) and co-express selected stem cell markers (Sox9, Tcf4 and Lgr5). Lhx2+ cells represent the vast majority of cells in the bulge and secondary hair germ that proliferate in response to skin injury. This is functionally important, since the wound re-epithelialization is significantly retarded in heterozygous Lhx2 knockout (+/-) mice, while anagen onset in the HFs located closely to the wound is accelerated compared to wild-type mice. Cell proliferation in the bulge and the number of Sox9+ and Tcf4+ cells in the HFs closely adjacent to the wound in Lhx2+/- mice are decreased in comparison to wild-type controls, while expression of Lgr5 and cell proliferation in the secondary hair germ are increased. Furthermore, acceleration of wound-induced anagen development in Lhx2+/- mice is inhibited by administration of Lgr5 siRNA. In addition, Chip-on-chip/ChIP-qPCR and reporter assay analyses reveal Sox9, Tcf4 and Lgr5 as direct Lhx2 targets in keratinocytes. These data strongly suggest that Lhx2 positively regulates Sox9 and Tcf4 in the bulge cells and promotes wound re-epithelization, while it simultaneously negatively regulates Lgr5 in the secondary hair germ and inhibits HF cycling. Thus, Lhx2 operates as a regulator of epithelial stem cell activity during skin response to injury. Total RNA derived from Lhx2KO and WT embryos was subjected to a dual-color microarray analysis, in which the RNA from Lhx2KO embryo was labelled with Cy3 and that of WT embryo with Cy5 respectivly
2011-10-03 | E-GEOD-32511 | biostudies-arrayexpress
Project description:The Lhx2 transcription factor plays essential roles in morphogenesis and patterning of ectodermal derivatives, as well as in controlling stem cell activity. Lhx2 is expressed in the hair follicle (HF) buds, while in postnatal telogen HFs Lhx2+ cells reside in the stem cell-enriched epithelial compartments (bulge, secondary hair germ) and co-express selected stem cell markers (Sox9, Tcf4 and Lgr5). Lhx2+ cells represent the vast majority of cells in the bulge and secondary hair germ that proliferate in response to skin injury. This is functionally important, since the wound re-epithelialization is significantly retarded in heterozygous Lhx2 knockout (+/-) mice, while anagen onset in the HFs located closely to the wound is accelerated compared to wild-type mice. Cell proliferation in the bulge and the number of Sox9+ and Tcf4+ cells in the HFs closely adjacent to the wound in Lhx2+/- mice are decreased in comparison to wild-type controls, while expression of Lgr5 and cell proliferation in the secondary hair germ are increased. Furthermore, acceleration of wound-induced anagen development in Lhx2+/- mice is inhibited by administration of Lgr5 siRNA. In addition, Chip-on-chip/ChIP-qPCR and reporter assay analyses reveal Sox9, Tcf4 and Lgr5 as direct Lhx2 targets in keratinocytes. These data strongly suggest that Lhx2 positively regulates Sox9 and Tcf4 in the bulge cells and promotes wound re-epithelization, while it simultaneously negatively regulates Lgr5 in the secondary hair germ and inhibits HF cycling. Thus, Lhx2 operates as a regulator of epithelial stem cell activity during skin response to injury.
2011-10-04 | GSE32511 | GEO
Project description:Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that Tbr1, a transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. Tbr1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in Tbr1 mutants. Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. Tbr1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, Tbr1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons.
2010-07-27 | GSE22371 | GEO
Project description:Expression of the lim-homeodomain transcription factor is required for sustained maintenance of heamatopoietic stem cell like cells in undifferentiated form durng in vitro culturing. Cell lines were created from the mouse embryonic stem (ES) cell line, Ainv15. The gene Lhx2 was introducted into these cells under the control of a tetracycline-responsive element. In the presence of tetracycline (or its analogue doxycycline), these cells express Lhx2. In DoxHPC7 GFP is co-expressed together with the Lhx2 gene. We used these cells to carry out a time-course study where the effects of Lhx2 withdrawal were studied.
2005-12-19 | E-MEXP-431 | biostudies-arrayexpress