Identification and Characterization of LHX8 DNA Binding Elements

Park, Miree; Jeon, Sanghyun; Jeong, Jihye; Park, Miseon; Lee, Dong-Ryul; Yoon, Tae Ki; Choi, Dong Hee; Choi, Yun‐Sang

doi:10.12717/dr.2012.16.4.379

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…Consistent with its function in meiosis, in Lhx8-/-ovaries we observed dysregulation of Msx1, a gene involved in promoting meiosis [49] and identified as a putative target of LHX8 [11] (Figure 2G), and another initiator of meiosis, Stra8, was earlier reported to be upregulated [10]. Furthermore, SPO11, directly involved in the induction of DNA breaks for recombination during meiosis [50], was also dysregulated at P0 in Lhx8-/-ovaries ( Figure 2G); thus, significant DNA damage was still ongoing at that stage.…”

Section: Dna Damage and Autophagysupporting

confidence: 78%

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Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

D'Ignazio

Michel

Beyer

et al. 2018

Biology of Reproduction

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Following proliferation of oogonia in mammals, great numbers of germ cells are discarded, primarily by apoptosis, while the remainder form primordial follicles (the ovarian reserve) that determine fertility and reproductive lifespan. More massive, rapid, and essentially total loss of oocytes, however, occurs when the transcription factor Lhx8 is ablated-though the cause and mechanism of germ cell loss from the Lhx8-/-ovaries has been unknown. We found that Lhx8−/− ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth. The loss results from activation of autophagy, which becomes overwhelming within the first postnatal week, with extracellular matrix proteins filling the space previously occupied by follicles to produce a fibrotic ovary. Associated with this process, as early as a few days before birth, Lhx8-/-oocytes failed to repair DNA damage-which normally occurs when meiosis is initiated during embryonic development; and DNA damage repair genes were downregulated throughout the oocyte short lifespan. Based on gene expression analyses and morphological changes, we propose a model in which lineage-restricted failure of DNA repair triggers germ cell autophagy, causing premature depletion of the ovarian reserve in Lhx8-/-mice. Summary SentenceAblation of Lhx8 causes premature loss of germ cells by autophagy associated with impairment of DNA damage repair during meiosis.

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Section: Dna Damage and Autophagysupporting

confidence: 78%

“…Recent in vitro analyses have identified TGATTG as the core of a putative LHX8 DNA-binding sequence and showed that LHX8 directly regulates the transcription of several genes including germ cell-specific Nobox [11]. The mechanism of action of Lhx8 and the cause of oocyte death in its absence have, however, been unresolved.…”

Section: Introductionmentioning

confidence: 99%

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

D'Ignazio

Michel

Beyer

et al. 2018

Biology of Reproduction

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“…Based on bioinformatics analysis and promoter deletion analysis of this study, we found that within the −427 to −376 bp region of the pig BMP15 promoter there exists sites for transcription factors LHX8, NOBOX, and PITX1, which are the potential positive regulators to activate pig BMP15 . Although LHX8 , NOBOX , BMP15, and GDF9 are highly expressed during ovarian follicle development [ 25 , 35 ], the definite regulatory network among these genes is under investigation. Several studies have reported an association between the BMP15 and premature ovarian failure, showing that the variant BMP15 c.-9 C>G results in modification of its binding sites for PITX1 that trans-activates BMP15 promoter and increases the recruitment of an elevated number of follicles/oocytes early in a woman’s life [ 18 , 30 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Analysis of Regulatory Elements in Porcine Bone Morphogenetic Protein 15 Gene Promoter

Wan¹,

Wang²,

Wang³

2015

IJMS

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Bone morphogenetic protein 15 (BMP15) is secreted by the mammalian oocytes and is indispensable for ovarian follicular development, ovulation, and fertility. To determine the regulation mechanism of BMP15 gene, the regulatory sequence of porcine BMP15 was investigated in this study. The cloned BMP15 promoter retains the cell-type specificity, and is activated in cells derived from ovarian tissue. The luciferase assays in combination with a series of deletion of BMP15 promoter sequence show that the −427 to −376 bp region of BMP15 promoter is the primary regulatory element, in which there are a number of transcription factor binding sites, including LIM homeobox 8 (LHX8), newborn ovary homeobox gene (NOBOX), and paired-like homeodomain transcription factor 1 (PITX1). Determination of tissue-specific expression reveals that LHX8, but not PITX1 and NOBOX, is exclusively expressed in pig ovary tissue and is translocated into the cell nuclei. Overexpression of LHX8 in Chinese hamster ovary (CHO) cells could significantly promote BMP15 promoter activation. This study confirms a key regulatory element that is located in the proximal region of BMP15 promoter and is regulated by the LHX8 factor.

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“…Cholinergic neurons are derived from progenitor cells in the MGE, where LHX8 promotes the expression of Isl1 upon cholinergic commitment, which in turn represses Lhx6 expression ( Zhao et al, 2003 ). Lhx8 forms a hexamer with Isl1 and promotes cholinergic neuron expression by binding to specific motifs in the cholinergic enhancer sequence ( Park et al, 2012 ). The formation of hexamers is necessary for DNA binding and subsequently cholinergic gene expression, whilst LHX8 or ISL1 alone does not bind to cholinergic enhancer sequences and are unable to promote cholinergic interneuron differentiation ( Cho et al, 2014 ).…”

Section: Selected Transcription Factors Encoded By Homeobox Genesmentioning

confidence: 99%

Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

et al. 2022

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Forebrain development in vertebrates is regulated by transcription factors encoded by homeobox, bHLH and forkhead gene families throughout the progressive and overlapping stages of neural induction and patterning, regional specification and generation of neurons and glia from central nervous system (CNS) progenitor cells. Moreover, cell fate decisions, differentiation and migration of these committed CNS progenitors are controlled by the gene regulatory networks that are regulated by various homeodomain-containing transcription factors, including but not limited to those of the Pax (paired), Nkx, Otx (orthodenticle), Gsx/Gsh (genetic screened), and Dlx (distal-less) homeobox gene families. This comprehensive review outlines the integral role of key homeobox transcription factors and their target genes on forebrain development, focused primarily on the telencephalon. Furthermore, links of these transcription factors to human diseases, such as neurodevelopmental disorders and brain tumors are provided.

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Identification and Characterization of LHX8 DNA Binding Elements

Cited by 7 publications

References 11 publications

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

Identification and Analysis of Regulatory Elements in Porcine Bone Morphogenetic Protein 15 Gene Promoter

Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

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