LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1

Hou, Pei Shan; Chuang, Ching Yu; Kao, Cheng Fu; Chou, Shen Ju; Stone, Lee; Ho, Hong Nerng; Chien, Chung‐Liang; Kuo, Hung-Chih

doi:10.1093/nar/gkt567

Cited by 61 publications

(60 citation statements)

References 63 publications

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“…It has been suggested that NC competence segregates with the neuralized domain of the ectoderm (Pieper et al, 2012;Schlosser, 2008). We have examined the expression dynamics of a number of neural-related transcripts, including LHX2, PAX6, SOX1, SOX2, OTX2 and HES5 (Greber et al, 2011;Hou et al, 2013;Zhang et al, 2010). Variable and mild (∼10-fold or less) increases in expression were observed in only a subset of these genes (PAX6, SOX1, SOX2, OTX2) and others were not induced at all (LHX2 and HES5).…”

Section: Discussionmentioning

confidence: 99%

“…The neural induction program in human embryos and ESCs has been studied (Greber et al, 2011;Hou et al, 2013;Zhang et al, 2010). Although there was transient and variable upregulation of the pluripotency/neural markers SOX2, SOX1 and OTX2 during our NC cell induction, other pre-neural and mature neural progenitor markers, such as LHX2 and HES5, were never induced (data not shown; Fig.…”

Section: Human Neural Crest Induction Requires An Early and Balanced mentioning

confidence: 95%

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WNT/β-catenin signaling mediates human neural crest induction via a pre-neural border intermediate

et al. 2016

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Neural crest (NC) cells arise early in vertebrate development, migrate extensively and contribute to a diverse array of ectodermal and mesenchymal derivatives. Previous models of NC formation suggested derivation from neuralized ectoderm, via meso-ectodermal, or neural-non-neural ectoderm interactions. Recent studies using bird and amphibian embryos suggest an earlier origin of NC, independent of neural and mesodermal tissues. Here, we set out to generate a model in which to decipher signaling and tissue interactions involved in human NC induction. Our novel human embryonic stem cell (ESC)-based model yields high proportions of multipotent NC cells (expressing SOX10, PAX7 and TFAP2A) in 5 days. We demonstrate a crucial role for WNT/β-catenin signaling in launching NC development, while blocking placodal and surface ectoderm fates. We provide evidence of the delicate temporal effects of BMP and FGF signaling, and find that NC development is separable from neural and/ or mesodermal contributions. We further substantiate the notion of a neural-independent origin of NC through PAX6 expression and knockdown studies. Finally, we identify a novel pre-neural border state characterized by early WNT/β-catenin signaling targets that displays distinct responses to BMP and FGF signaling from the traditional neural border genes. In summary, our work provides a fast and efficient protocol for human NC differentiation under signaling constraints similar to those identified in vivo in model organisms, and strengthens a framework for neural crest ontogeny that is separable from neural and mesodermal fates.

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Section: Discussionmentioning

confidence: 99%

Section: Human Neural Crest Induction Requires An Early and Balanced mentioning

confidence: 95%

WNT/β-catenin signaling mediates human neural crest induction via a pre-neural border intermediate

et al. 2016

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“…Mediated through its DNA-binding homeodomain, Lhx2 controls hundreds of downstream genes directly (34,35). We next aimed to identify molecules that are relevant to cortical area patterning and, mediated by its protein-binding LIM domain (36), interact biochemically with Lhx2.…”

Section: Significancementioning

confidence: 99%

Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2

Zembrzycki

Pérez-García

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.terminal selector genes | epigenetic mechanisms | neuronal fate | MeCP2 | CoupTF1T he adult mammalian cortex is patterned into distinct and modality-specific sensory areas that are responsible for the perception of the sensory information and for the control of behavior (1). Research has focused in particular on how transcription factors (TFs), which are expressed in gradients in the cortical ventricular zone (VZ) progenitors, drive area patterning of mature cortical sensory areas by specifying their size and position during early cortical development (1, 2). As a result, current views suggest that the specification of sensory area identity is dominated by patterning events in progenitors (1-3). However, the mechanisms that translate area-patterning information from cortical progenitors into area-specific properties of postmitotic (CP) neurons are not well understood. ResultsWe hypothesized that sensory area identity in CP neurons in mice could be determined ultimately by the function of key regulators that function postmitotically. One of the few TFs that are expressed in progenitors and neurons is LIM-homeodomain 2 (Lhx2) (4). During early corticogenesis, Lhx2 shows a caudal/ medial-high to rostral/lateral-low expression gradient in cortical progenitors. Starting from around embryonic day (E) 12 to postnatal day (P) 0, a caudal/lateral-high to rostral/medial-low expression gradient is apparent in cortical neurons (Fig. S1), which postnatally becomes restricted to more uniform expression in upper cortical layers (Fig. S1). Such sustained and dynamic expression of Lhx2 in neurons suggests that Lhx2, similarly to its established roles exerted in progenitors (4-8), may affect properties in cortical neurons...

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“…20 Hou et al demonstrated that Lhx2 binds to enhancers rather than the promoter of PAX6 to induce neural differentiation from human embryonic stem cells. 21 Also, the LIM domain of Lhx2 functions as a coactivator through interaction with MRG1, leading to recruitment of p300/CBP to stimulate glycoprotein hormone a-subunit gene expression. 22 On the other hand, Lhx2 negatively regulates the PRL promoter in pituitary cell lines by an as yet unknown mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Lhx2 activates antagonists of WNT and BMP protein in certain areas to inhibit these signaling pathways in the developing forebrain. 21,24 Because WNT and BMP signaling are involved in osteoblast differentiation and bone formation, we examined whether Lhx2 directly affects osteoblast differentiation and function. 25 Overexpression of Lhx2 in osteoblasts showed a marginal effect on BMP2-mediated osteoblast differentiation and nodule formation (Figures 2c and d).…”

Section: Discussionmentioning

confidence: 99%

Lhx2 regulates bone remodeling in mice by modulating RANKL signaling in osteoclasts

et al. 2014

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The LIM homeobox 2 (Lhx2) transcription factor Lhx2 has a variety of functions, including neural induction, morphogenesis, and hematopoiesis. Here we show the involvement of Lhx2 in osteoclast differentiation. Lhx2 was strongly expressed in osteoclast precursor cells but its expression was significantly reduced during receptor activator of nuclear factor-jB ligand (RANKL)-mediated osteoclastogenesis. Overexpression of Lhx2 in bone marrow-derived monocyte/macrophage lineage cells (BMMs), which are osteoclast precursor cells, attenuated RANKL-induced osteoclast differentiation by inhibiting the induction of nuclear factor of activated T cells c1 (NFATc1). Interestingly, interaction of Lhx2 proteins with c-Fos attenuated the DNA-binding ability of c-Fos and thereby inhibited the transactivation of NFATc1. Furthermore, Lhx2 conditional knockout mice exhibited an osteoporotic bone phenotype, which was related with increased osteoclast formation in vivo. Taken together, our results suggest that Lhx2 acts as a negative regulator of osteoclast formation in vitro and in vivo. The anti-osteoclastogenic effect of Lhx2 may be useful for developing a therapeutic strategy for bone disease.

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LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1

Cited by 61 publications

References 63 publications

WNT/β-catenin signaling mediates human neural crest induction via a pre-neural border intermediate

WNT/β-catenin signaling mediates human neural crest induction via a pre-neural border intermediate

Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2

Lhx2 regulates bone remodeling in mice by modulating RANKL signaling in osteoclasts

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