Homeobox B9 integrates bone morphogenic protein 4 with inflammation at atheroprone sites

Abstract Aims Atherosclerosis develops near branches and bends of arteries that are exposed to disturbed blood flow which exerts low wall shear stress (WSS). These mechanical conditions alter endothelial cells (EC) by priming them for inflammation and by inducing turnover. Homeobox (Hox) genes are developmental genes involved in the patterning of embryos along their anterior–posterior and proximal–distal axes. Here we identified Hox genes that are regulated by WSS and investigated their functions in adult arteries. Methods and results EC were isolated from inner (low WSS) and outer (high WSS) regions of the porcine aorta and the expression of Hox genes was analysed by quantitative real-time PCR. Several Hox genes (HoxA10, HoxB4, HoxB7, HoxB9, HoxD8, HoxD9) were significantly enriched at the low WSS compared to the high WSS region. Similarly, studies of cultured human umbilical vein EC (HUVEC) or porcine aortic EC revealed that the expression of multiple Hox genes (HoxA10, HoxB9, HoxD8, HoxD9) was enhanced under low (4 dyn/cm2) compared to high (13 dyn/cm2) WSS conditions. Gene silencing studies identified Hox genes (HoxB9, HoxD8, HoxD9) that are positive regulators of inflammatory molecule expression in EC exposed to low WSS, and others (HoxB9, HoxB7, HoxB4) that regulated EC turnover. We subsequently focused on HoxB9 because it was strongly up-regulated by low WSS and, uniquely, was a driver of both inflammation and proliferation. At a mechanistic level, we demonstrate using cultured EC and murine models that bone morphogenic protein 4 (BMP4) is an upstream regulator of HoxB9 which elicits inflammation via induction of numerous inflammatory mediators including TNF and downstream NF-κB activation. Moreover, the BMP4-HoxB9-TNF pathway was potentiated by hypercholesterolaemic conditions. Conclusions Low WSS induces multiple Hox genes that control the activation state and turnover of EC. Notably, low WSS activates a BMP4-HoxB9-TNF signalling pathway to initiate focal arterial inflammation, thereby demonstrating integration of the BMP and Hox systems in vascular pathophysiology.

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Faculty Opinions recommendation of Bone morphogenic protein antagonists are coexpressed with bone morphogenic protein 4 in endothelial cells exposed to unstable flow in vitro in mouse aortas and in human coronary arteries: role of bone morphogenic protein antagonists in inflammation and atherosclerosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1092378.546807 ◽

2007 ◽

Author(s):

Cam Patterson

Keyword(s):

Endothelial Cells ◽

Coronary Arteries ◽

Bone Morphogenic Protein ◽

Unstable Flow ◽

Bone Morphogenic Protein 4

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Hox genes are essential for the development of eyespots in Bicyclus anynana butterflies

Genetics ◽

10.1093/genetics/iyaa005 ◽

2020 ◽

Vol 217 (1) ◽

Author(s):

Yuji Matsuoka ◽

Antónia Monteiro

Keyword(s):

Hox Genes ◽

Bicyclus Anynana ◽

Hox Gene ◽

Novel Traits ◽

Anterior Posterior ◽

Anterior Posterior Axis

Abstract The eyespot patterns found on the wings of nymphalid butterflies are novel traits that originated first in hindwings and subsequently in forewings, suggesting that eyespot development might be dependent on Hox genes. Hindwings differ from forewings in the expression of Ultrabithorax (Ubx), but the function of this Hox gene in eyespot development as well as that of another Hox gene Antennapedia (Antp), expressed specifically in eyespots centers on both wings, are still unclear. We used CRISPR-Cas9 to target both genes in Bicyclus anynana butterflies. We show that Antp is essential for eyespot development on the forewings and for the differentiation of white centers and larger eyespots on hindwings, whereas Ubx is essential not only for the development of at least some hindwing eyespots but also for repressing the size of other eyespots. Additionally, Antp is essential for the development of silver scales in male wings. In summary, Antp and Ubx, in addition to their conserved roles in modifying serially homologous segments along the anterior–posterior axis of insects, have acquired a novel role in promoting the development of a new set of serial homologs, the eyespot patterns, in both forewings (Antp) and hindwings (Antp and Ubx) of B. anynana butterflies. We propose that the peculiar pattern of eyespot origins on hindwings first, followed by forewings, could be due to an initial co-option of Ubx into eyespot development followed by a later, partially redundant, co-option of Antp into the same network.

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Hox genes and the evolution of vertebrate axial morphology

Development ◽

10.1242/dev.121.2.333 ◽

1995 ◽

Vol 121 (2) ◽

pp. 333-346 ◽

Cited By ~ 55

Author(s):

A.C. Burke ◽

C.E. Nelson ◽

B.A. Morgan ◽

C. Tabin

Keyword(s):

Hox Genes ◽

Cervical Vertebrae ◽

Homeobox Gene ◽

Paraxial Mesoderm ◽

Thoracic Vertebrae ◽

Homeotic Genes ◽

Evolutionary Variation ◽

Axial Morphology ◽

Anterior Posterior ◽

Anterior Posterior Axis

A common form of evolutionary variation between vertebrate taxa is the different numbers of segments that contribute to various regions of the anterior-posterior axis; cervical vertebrae, thoracic vertebrae, etc. The term ‘transposition’ is used to describe this phenomenon. Genetic experiments with homeotic genes in mice have demonstrated that Hox genes are in part responsible for the specification of segmental identity along the anterior-posterior axis, and it has been proposed that an axial Hox code determines the morphology of individual vertebrae (Kessel, M. and Gruss, P. (1990) Science 249, 347–379). This paper presents a comparative study of the developmental patterns of homeobox gene expression and developmental morphology between animals that have homologous regulatory genes but different morphologies. The axial expression boundaries of 23 Hox genes were examined in the paraxial mesoderm of chick, and 16 in mouse embryos by in situ hybridization and immunolocalization techniques. Hox gene anterior expression boundaries were found to be transposed in concert with morphological boundaries. This data contributes a mechanistic level to the assumed homology of these regions in vertebrates. The recognition of mechanistic homology supports the historical homology of basic patterning mechanisms between all organisms that share these genes.

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Roles of Drosophila Hox Genes in the Assembly of Neuromuscular Networks and Behavior

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.786993 ◽

2022 ◽

Vol 9 ◽

Author(s):

Rohit Joshi ◽

Rashmi Sipani ◽

Asif Bakshi

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Motor Neuron ◽

Hox Genes ◽

Neural Circuitry ◽

Neuron Morphology ◽

Developing Region ◽

And Behavior ◽

Anterior Posterior

Hox genes have been known for specifying the anterior-posterior axis (AP) in bilaterian body plans. Studies in vertebrates have shown their importance in developing region-specific neural circuitry and diversifying motor neuron pools. In Drosophila, they are instrumental for segment-specific neurogenesis and myogenesis early in development. Their robust expression in differentiated neurons implied their role in assembling region-specific neuromuscular networks. In the last decade, studies in Drosophila have unequivocally established that Hox genes go beyond their conventional functions of generating cellular diversity along the AP axis of the developing central nervous system. These roles range from establishing and maintaining the neuromuscular networks to controlling their function by regulating the motor neuron morphology and neurophysiology, thereby directly impacting the behavior. Here we summarize the limited knowledge on the role of Drosophila Hox genes in the assembly of region-specific neuromuscular networks and their effect on associated behavior.

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PS 04-09 HIGH GLUCOSE AND PALMITATE INCREASES BONE MORPHOGENIC PROTEIN 4 EXPRESSION IN HUMAN ENDOTHELIAL CELLS

Journal of Hypertension ◽

10.1097/01.hjh.0000500245.67918.ba ◽

2016 ◽

Vol 34 (Supplement 1) ◽

pp. e136

Author(s):

Hyuk Sang Kwon ◽

Oak Kee Hong ◽

Jang Won Son ◽

Soon Jib Yoo ◽

Ki Ho Song ◽

...

Keyword(s):

Endothelial Cells ◽

High Glucose ◽

Bone Morphogenic Protein ◽

Human Endothelial Cells ◽

Bone Morphogenic Protein 4

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Expression of bone morphogenic protein-4 is inversely related to prevalence of lymph node metastasis in gastric adenocarcinoma

Surgery Today ◽

10.1007/s00595-010-4320-2 ◽

2011 ◽

Vol 41 (5) ◽

pp. 688-692 ◽

Cited By ~ 6

Author(s):

Seong-Gon Kim ◽

Hye-Rim Park ◽

Soo-Kee Min ◽

Je-Yong Choi ◽

Sung-Hoon Koh ◽

...

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Gastric Adenocarcinoma ◽

Bone Morphogenic Protein ◽

Node Metastasis ◽

Bone Morphogenic Protein 4

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Protein kinase C βII and δ/θ play critical roles in bone morphogenic protein-4-stimulated osteoblastic differentiation of MC3T3-E1 cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2010.10.074 ◽

2010 ◽

Vol 403 (1) ◽

pp. 7-12 ◽

Cited By ~ 11

Author(s):

Ki Ho Park ◽

Dong In Han ◽

Yun-Hee Rhee ◽

Soo-Jin Jeong ◽

Sung-Hoon Kim ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Osteoblastic Differentiation ◽

Bone Morphogenic Protein ◽

Kinase C ◽

Bone Morphogenic Protein 4

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Platelet Derived Growth Factor (PDGF) and Bone Morphogenic Protein 4 (BMP4) Levels May Indicate Presence of Combined Pre and Post Capillary WHO Group II Pulmonary Hypertension

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2019.01.1251 ◽

2019 ◽

Vol 38 (4) ◽

pp. S492

Author(s):

H. Marcos-Abdala ◽

H. Karmouty-Quintana ◽

K. Youker ◽

A. Cruz-Solbes ◽

J. Amione-Guerra ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Growth Factor ◽

Bone Morphogenic Protein ◽

Platelet Derived Growth Factor ◽

Group Ii ◽

Bone Morphogenic Protein 4

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Transcriptional Trajectories in Mouse Limb Buds Reveal the Transition from Anterior-Posterior to Proximal-Distal Patterning at Early Limb Bud Stage

Journal of Developmental Biology ◽

10.3390/jdb8040031 ◽

2020 ◽

Vol 8 (4) ◽

pp. 31

Author(s):

Ines Desanlis ◽

Rachel Paul ◽

Marie Kmita

Keyword(s):

Global Change ◽

Hox Genes ◽

Limb Bud ◽

Temporal Expression ◽

Distal Limb ◽

Limb Patterning ◽

Previous Evidence ◽

Limb Mesenchyme ◽

Mouse Limb ◽

Anterior Posterior

Limb patterning relies in large part on the function of the Hox family of developmental genes. While the differential expression of Hox genes shifts from the anterior–posterior (A–P) to the proximal–distal (P–D) axis around embryonic day 11 (E11), whether this shift coincides with a more global change of A–P to P–D patterning program remains unclear. By performing and analyzing the transcriptome of the developing limb bud from E10.5 to E12.5, at single-cell resolution, we have uncovered transcriptional trajectories that revealed a general switch from A–P to P–D genetic program between E10.5 and E11.5. Interestingly, all the transcriptional trajectories at E10.5 end with cells expressing either proximal or distal markers suggesting a progressive acquisition of P–D identity. Moreover, we identified three categories of genes expressed in the distal limb mesenchyme characterized by distinct temporal expression dynamics. Among these are Hoxa13 and Hoxd13 (Hox13 hereafter), which start to be expressed around E10.5, and importantly the binding of the HOX13 factors was observed within or in the neighborhood of several of the distal limb genes. Our data are consistent with previous evidence suggesting that the transition from the early/proximal to the late/distal transcriptome of the limb mesenchyme largely relies on HOX13 function. Based on these results and the evidence that HOX13 factors restrict Hoxa11 expression to the proximal limb, in progenitor cells of the zeugopod, we propose that HOX13 act as a key determinant of P–D patterning.

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