Lhx1/5 control dendritogenesis and spine morphogenesis of Purkinje cells via regulation of Espin

Lui, Kathy Nga-Chu; Tam, Wing Yip; Gao, Caiji; Huang, Jiandong; Wang, Chi Chiu; Jiang, Liwen; Yung, Wing‐Ho; Kwan, Kin Ming

doi:10.1038/ncomms15079

Cited by 26 publications

(25 citation statements)

References 55 publications

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“…To characterize pancreatic Lhx1 expression, we employed the use of Lhx1 knock-in LacZ reporter (24) mouse pancreata for histological analysis. LacZ reporter staining of E14.5 whole embryos demonstrated Lhx1 mRNA expression in the central nervous system, as expected (34,59) (see whole mount stained embryos Fig. 1A, inset).…”

Section: Lhx1 Is Expressed In ␤-Cell Lines and In The Developing And supporting

confidence: 66%

The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

Bethea

Liu

Wade

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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The LIM-homeodomain (LIM-HD) transcription factor Islet-1 (Isl1) interacts with the LIM domain-binding protein 1 (Ldb1) coregulator to control expression of key pancreatic β-cell genes. However, Ldb1 also has Isl1-independent effects, supporting that another LIM-HD factor interacts with Ldb1 to impact β-cell development and/or function. LIM homeobox 1 (Lhx1) is an Isl1-related LIM-HD transcription factor that appears to be expressed in the developing mouse pancreas and in adult islets. However, roles for this factor in the pancreas are unknown. This study aimed to determine Lhx1 interactions and elucidate gene regulatory and physiological roles in the pancreas. Co-immunoprecipitation using β-cell extracts demonstrated an interaction between Lhx1 and Isl1, and thus we hypothesized that Lhx1 and Isl1 regulate similar target genes. To test this, we employed siRNA-mediated Lhx1 knockdown in β-cell lines and discovered reduced Glp1R mRNA. Chromatin immunoprecipitation revealed Lhx1 occupancy at a domain also known to be occupied by Isl1 and Ldb1. Through development of a pancreas-wide knockout mouse model ( Lhx1∆Panc), we demonstrate that aged Lhx1∆Panc mice have elevated fasting blood glucose levels, altered intraperitoneal and oral glucose tolerance, and significantly upregulated glucagon, somatostatin, pancreatic polypeptide, MafB, and Arx islet mRNAs. Additionally, Lhx1∆Panc mice exhibit significantly reduced Glp1R, an mRNA encoding the insulinotropic receptor for glucagon-like peptide 1 along with a concomitant dampened Glp1 response and mild glucose intolerance in mice challenged with oral glucose. These data are the first to reveal that the Lhx1 transcription factor contributes to normal glucose homeostasis and Glp1 responses.

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Section: Lhx1 Is Expressed In ␤-Cell Lines and In The Developing And supporting

confidence: 66%

The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

Bethea

Liu

Wade

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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“…The mes/r1 neuroepithelium ChIP was performed according to previous literatures [ 68 , 69 ]. Generally, after removal of the embryonic skin, 4–5 wildtype C57/Bl6 E10.5 mouse mes/r1 neural tubes were dissected and pooled into ice-cold PBS.…”

Section: Methodsmentioning

confidence: 99%

Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis

Dong

Kwan

2020

Mol Brain

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The highly conserved and ubiquitously expressed transcription factor Yin Yang 1 ( Yy1 ), was named after its dual functions of both activating and repressing gene transcription. Yy1 plays complex roles in various fundamental biological processes such as the cell cycle progression, cell proliferation, survival, and differentiation. Patients with dominant Yy1 mutations suffer from central nervous system (CNS) developmental defects. However, the role of Yy1 in mammalian CNS development remains to be fully elucidated. The isthmus organizer locates to the mid-hindbrain (MHB) boundary region and serves as the critical signaling center during midbrain and cerebellar early patterning. To study the function of Yy1 in mesencephalon/ rhombomere 1 (mes/r1) neuroepithelium development, we utilized the tissue-specific Cre-LoxP system and generated a conditional knockout mouse line to inactivate Yy1 in the MHB region. Mice with Yy1 deletion in the mes/r1 region displayed cerebellar agenesis and dorsal midbrain hypoplasia. The Yy1 deleted neuroepithelial cells underwent cell cycle arrest and apoptosis, with the concurrent changes of cell cycle regulatory genes expression, as well as activation of the p53 pathway. Moreover, we found that Yy1 is involved in the transcriptional activation of Wnt1 in neural stem cells. Thus, our work demonstrates the involvement of Yy1 in cerebellar agenesis and the critical function of Yy1 in mouse early MHB neuroepithelium maintenance and development.

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“…Most of the Utx gene mutations in humans disrupt its role in histone demethylation and even result in Kabuki syndrome, a pediatric congenital disorder with multiple congenital anomalies and intellectual disabilities ( Kim and Lee, 2017 , Morales Torres et al., 2013 , Shpargel et al., 2012 ). Sometimes UTX exerts its function independent of its H3K27 demethylase activity ( Lui et al., 2017 , Shpargel et al., 2014 , Yoo et al., 2016 ). Overall, UTX participates in the regulation of embryonic development both dependent on and independent of its demethylase activity.…”

Section: Introductionmentioning

confidence: 99%

UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling

Lei

Jiao

2018

Stem Cell Reports

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SummaryNeural stem cell (NSC) proliferation and differentiation in the developing brain is a complex process precisely regulated by intrinsic and extrinsic signals. Although epigenetic modification has been reportedly involved in the regulation of the cerebral cortex, whether UTX, an H3K27me3 demethylase, regulates the development of cerebral cortex during the embryonic period is unclear. In this study, we demonstrate that Utx deficiency by knockdown and conditional knockout increases NSC proliferation and decreases terminal mitosis and neuronal differentiation. Furthermore, we find that impairment of cortical development caused by lack of Utx is less significant in males than in females. In addition, UTX demethylates H3K27me3 at the Pten promoter and promotes Pten expression. P-AKT and P-mTOR levels are increased in the Utx conditional knockout cortices. Finally, Utx or Pten overexpression can rescue the impairment of brain development caused by Utx loss. These findings may provide important clues toward deciphering brain diseases.

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Lhx1/5 control dendritogenesis and spine morphogenesis of Purkinje cells via regulation of Espin

Cited by 26 publications

References 55 publications

The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis

UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling

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