Lhx9 gene expression during early limb development in mice requires the FGF signalling pathway

Yang, Ying; Wilson, Megan J.

doi:10.1016/j.gep.2015.07.002

Cited by 22 publications

(21 citation statements)

References 26 publications

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“…Although the pattern of Lhx2 and Lhx9 expression in mice is consistent with regulation by FGF, Tzchori et al suggested that Fgf4/8 did not control their expression [ 30 ]. In contrast, Yang and colleagues showed that Fgf signaling was required for Lhx9 expression in mouse limb explants [ 71 ]. In chicken, we demonstrate by transcriptome, WMISH, and RT-qPCR that FGF robustly upregulates LHX2 , but not LHX9 .…”

Section: Discussionmentioning

confidence: 99%

LHX2 Mediates the FGF-to-SHH Regulatory Loop during Limb Development

Watson

Feenstra

Arsdale

et al. 2018

JDB

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During limb development, fibroblast growth factors (Fgfs) govern proximal–distal outgrowth and patterning. FGFs also synchronize developmental patterning between the proximal–distal and anterior–posterior axes by maintaining Sonic hedgehog (Shh) expression in cells of the zone of polarizing activity (ZPA) in the distal posterior mesoderm. Shh, in turn, maintains Fgfs in the apical ectodermal ridge (AER) that caps the distal tip of the limb bud. Crosstalk between Fgf and Shh signaling is critical for patterned limb development, but the mechanisms underlying this feedback loop are not well-characterized. Implantation of Fgf beads in the proximal posterior limb bud can maintain SHH expression in the former ZPA domain (evident 3 h after application), while prolonged exposure (24 h) can induce SHH outside of this domain. Although temporally and spatially disparate, comparative analysis of transcriptome data from these different populations accentuated genes involved in SHH regulation. Comparative analysis identified 25 candidates common to both treatments, with eight linked to SHH expression or function. Furthermore, we demonstrated that LHX2, a LIM Homeodomain transcription factor, is an intermediate in the FGF-mediated regulation of SHH. Our data suggest that LHX2 acts as a competency factor maintaining distal posterior SHH expression subjacent to the AER.

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Section: Discussionmentioning

confidence: 99%

LHX2 Mediates the FGF-to-SHH Regulatory Loop during Limb Development

Watson

Feenstra

Arsdale

et al. 2018

JDB

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“…Thus, Lhx9 is essential for steroidogenesis after organogenesis. Moreover, Lhx9 participates in CNS development, such as in the caudal forebrain (15), spinal cord interneurons (16), hypothalamic neurons (17), and the pineal gland (18), as well as in the formation of other organs, such as limbs (19) and the heart (20). Moreover, Lhx9 is related to gonadal sex differentiation in species that undergo temperature-dependent sex determination, such as the red-eared slider turtle (21) and chick differentiating gonads (22), other than mice.…”

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confidence: 99%

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Sun

Chu

et al. 2018

FASEB j.

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Testosterone is essential for spermatogenesis and the maintenance of secondary sexual characteristics in males. An important transcription factor, LIM-homeobox gene 9 (Lhx9) is indispensable for testis development and testosterone production; however, post-translational modifications of Lhx9 are largely unknown. Here, for the first time to our knowledge, we demonstrate that the level of Lhx9 protein increases in human chorionic gonadotropin-exposed Leydig cells and can be polyubiquitylated. We found that Smad ubiquitylation regulatory factor 1 (Smurf1), an E3 ubiquitin ligase, targets Lhx9 for ubiquitin-mediated proteasome degradation, thereby negatively modulating its function. Increasing Smurf1 decreases the level of Lhx9 and inhibits the Lhx9 transactivation capacity of steroidogenic factor 1 [nuclear receptor subfamily 5, group A, member 1 (NR5A1)]. In contrast, the depletion of Smurf1 leads to increased expression of Lhx9 protein and enhances testosterone biosynthesis-related gene transcripts [NR5A1, steroidogenic acute regulatory protein, CYP17A1, hydroxy-δ-5-steroid dehydrogenase, hydroxy-δ-5-steroid dehydrogenase isomerase 6, and hydroxysteroid (17-β) dehydrogenase 3] and testosterone production in Leydig cells. Furthermore, we found that Smurf1 knockout mice exhibit higher levels of Lhx9 protein and steroidogenesis, which leads to increased serum testosterone concentration. These findings reveal that Smurf1 promotes Lhx9 ubiquitylation and is involved in testosterone production in Leydig cells directly. Our results provide new insights into the molecular events that play a role in the homeostasis of testosterone levels and may provide a new target for testosterone regulation.-Hu, F., Zhu, Q., Sun, B., Cui, C., Li, C., Zhang, L. Smad ubiquitylation regulatory factor 1 promotes LIM-homeobox gene 9 degradation and represses testosterone production in Leydig cells.

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“…In this study, the full-length cDNA of Ch Lhx9 was cloned from the invertebrate C. hongkongensis , which shares conserved domain structure with homologs from other species. Previous studies show that Lhx9 is mainly expressed in the epithelium, developing limbs and the nervous system ( Bertuzzi et al, 1999 ; Mazaud et al, 2002 ; Tzchori et al, 2009 ; Yang and Wilson, 2015 ). However, we found Lhx9 to be specific and highly expressed in hemocytes of oyster ( Tong et al, 2015 ), which demonstrates a species-specific expression pattern during evolution.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Mechanism Underlying Pro-apoptotic Role of Hemocytes Specific Transcriptional Factor Lhx9 in Crassostrea hongkongensis

Zhou

Mao

et al. 2018

Front. Physiol.

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Hemocytes are the central organ of immune defense against pathogens by means of inflammation, phagocytosis, and encapsulation in mollusks. The well-functioning of the host immune system relies on the hemocytes’ task exertion and frequent renewal, but the underlying renewal mechanism remains elusive at the gene level. Here, we identified one transcription factor, LIM homeobox 9, in Crassostrea hongkongensis (ChLhx9) that could be involved in hemocyte apoptosis or renewal. ChLhx9 contains a homeodomain and two LIM domains. The expression profile of ChLhx9 showed that it was specific and had high expression in hemocytes, and it significantly increased under the bacterial challenge. RNA interference of ChLhx9 dramatically decreased the apoptosis rate of hemocytes when compared with a control group, which strongly implies its pro-apoptotic role in hemocytes. Furthermore, the genomic responses to the knockdown of ChLhx9 were examined through RNA-seq, which showed that multiple pathways associated with cell apoptosis, including the apoptosis pathway, hippo signal pathway and p53 signaling pathway, were significantly down-regulated. Meanwhile, seven of the key apoptotic genes were confirmed to be upregulated by ChLhx9, among which ChASPP1 (apoptosis stimulating protein of p53) was confirmed to induce hemocyte apoptosis strongly, which demonstrates that ChASPP1 was a downstream target mediated by ChLhx9 that caused apoptosis. In conclusion, tissue-specific transcription factor ChLhx9 induces hemocyte apoptosis through activating apoptotic genes or pathways, which could contribute to hemocyte renewal and immune defense in oysters.

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Lhx9 gene expression during early limb development in mice requires the FGF signalling pathway

Cited by 22 publications

References 26 publications

LHX2 Mediates the FGF-to-SHH Regulatory Loop during Limb Development

LHX2 Mediates the FGF-to-SHH Regulatory Loop during Limb Development

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

The Molecular Mechanism Underlying Pro-apoptotic Role of Hemocytes Specific Transcriptional Factor Lhx9 in Crassostrea hongkongensis

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