scholarly journals Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription factors and retinoic acid

Development ◽  
2020 ◽  
Vol 148 (1) ◽  
pp. dev193813
Author(s):  
Alejandra C. López-Delgado ◽  
Irene Delgado ◽  
Vanessa Cadenas ◽  
Fátima Sánchez-Cabo ◽  
Miguel Torres
Keyword(s):  
Transcription Factors ◽  
Retinoic Acid ◽  
Hox Genes ◽  
Feedback Regulation ◽  
Axial Skeleton ◽  
Paraxial Mesoderm ◽  
Hox Proteins ◽  
Skeletal Defects ◽  
Hox Protein ◽  
Anterior Posterior

ABSTRACTVertebrate axial skeletal patterning is controlled by co-linear expression of Hox genes and axial level-dependent activity of HOX protein combinations. MEIS transcription factors act as co-factors of HOX proteins and profusely bind to Hox complex DNA; however, their roles in mammalian axial patterning remain unknown. Retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors; however, whether this role is related to MEIS/HOX activity remains unknown. Here, we study the role of Meis in axial skeleton formation and its relationship to the RA pathway in mice. Meis elimination in the paraxial mesoderm produces anterior homeotic transformations and rib mis-patterning associated to alterations of the hypaxial myotome. Although Raldh2 and Meis positively regulate each other, Raldh2 elimination largely recapitulates the defects associated with Meis deficiency, and Meis overexpression rescues the axial skeletal defects in Raldh2 mutants. We propose a Meis-RA-positive feedback loop, the output of which is Meis levels, that is essential to establish anterior-posterior identities and patterning of the vertebrate axial skeleton.

scholarly journals Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription factors and retinoic acid

2020 ◽  
Author(s):  
Alejandra C. López-Delgado ◽  
Irene Delgado ◽  
Vanessa Cadenas ◽  
Fátima Sánchez-Cabo ◽  
Miguel Torres
Keyword(s):  
Transcription Factors ◽  
Retinoic Acid ◽  
Feedback Regulation ◽  
Axial Skeleton ◽  
Hox Proteins ◽  
Axial Patterning ◽  
Skeletal Defects ◽  
Hox Protein ◽  
Anterior Posterior

ABSTRACTVertebrate axial skeletal patterning is controlled by coordinated collinear expression of Hox genes and axial level-dependent activity of Hox protein combinations. Transcription factors of the Meis family act as cofactors of Hox proteins and profusely bind to Hox complex DNA, however their roles in mammalian axial patterning have not been established. Similarly, retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors, however, whether this role is related to Meis/Hox activity in axial patterning remains unknown. Here we study the role of Meis in axial skeleton formation and its relationship to the RA pathway by characterizing Meis1, Meis2 and Raldh2 mutant mice. Meis elimination produces axial skeleton defects without affecting Hox gene transcription, including vertebral homeotic transformations and rib mis-patterning associated to defects in the hypaxial myotome. While Raldh2 and Meis positively regulate each other, Raldh2 elimination largely recapitulates the defects associated to Meis-deficiency and Meis overexpression rescues the axial skeletal defects in Raldh2 mutants. We propose a Meis-RA positive feedback loop whose output is Meis levels and is essential to establish anterior-posterior identities and pattern of the vertebrate axial skeleton.

The lines gene of Drosophila is required for specific functions of the Abdominal-B HOX protein

Development ◽  
1998 ◽  
Vol 125 (7) ◽  
pp. 1269-1274 ◽  
Author(s):  
J. Castelli-Gair
Keyword(s):  
Hox Genes ◽  
Hox Proteins ◽  
Normal Functions ◽  
Transcriptional Cofactors ◽  
Segment Polarity ◽  
Direct Target ◽  
Hox Protein ◽  
Segment Polarity Gene ◽  
Anterior Posterior ◽  
Polarity Gene

The Hox genes encode homeobox transcription factors that control the formation of segment specific structures in the anterior-posterior axis. HOX proteins regulate the transcription of downstream targets acting both as repressors and as activators. Due to the similarity of their homeoboxes it is likely that much of the specificity of HOX proteins is determined by interaction with transcriptional cofactors, but few HOX cofactor proteins have yet been described. Here I present genetic evidence showing that lines, a segment polarity gene of Drosophila, is required for the function of the Abdominal-B protein. In lines mutant embryos Abdominal-B protein expression is normal but incapable of promoting its normal functions: formation of the posterior spiracles and specification of an eighth abdominal denticle belt. These defects arise because in lines mutant embryos the Abdominal-B protein cannot activate its direct target empty spiracles or other downstream genes while it can function as a repressor of Ultrabithorax and abdominal-A. The lines gene seems to be required exclusively for Abdominal-B but not for the function of other Hox genes.

Hox genes and the evolution of vertebrate axial morphology

Development ◽  
1995 ◽  
Vol 121 (2) ◽  
pp. 333-346 ◽  
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.

Retinoic acid, HOX genes and the anterior-posterior axis in chordates

BioEssays ◽  
1996 ◽  
Vol 18 (8) ◽  
pp. 613-616 ◽  
Author(s):  
Sebastian M. Shimeld
Keyword(s):  
Retinoic Acid ◽  
Hox Genes ◽  
Anterior Posterior ◽  
Anterior Posterior Axis

Hox repression of a target gene: extradenticle-independent, additive action through multiple monomer binding sites

Development ◽  
2002 ◽  
Vol 129 (13) ◽  
pp. 3115-3126 ◽  
Author(s):  
Ron Galant ◽  
Christopher M. Walsh ◽  
Sean B. Carroll
Keyword(s):  
Binding Sites ◽  
Target Gene ◽  
Target Genes ◽  
Hox Genes ◽  
Regulatory Element ◽  
Morphological Diversity ◽  
Hox Proteins ◽  
Cis Element ◽  
Additive Action ◽  
Hox Protein

Homeotic (Hox) genes regulate the identity of structures along the anterior-posterior axis of most animals. The low DNA-binding specificities of Hox proteins have raised the question of how these transcription factors selectively regulate target gene expression. The discovery that the Extradenticle (Exd)/Pbx and Homothorax (Hth)/Meis proteins act as cofactors for several Hox proteins has advanced the view that interactions with cofactors are critical to the target selectivity of Hox proteins. It is not clear, however, to what extent Hox proteins also regulate target genes in the absence of cofactors. In Drosophila melanogaster, the Hox protein Ultrabithorax (Ubx) promotes haltere development and suppresses wing development by selectively repressing many genes of the wing-patterning hierarchy, and this activity requires neither Exd nor Hth function. Here, we show that Ubx directly regulates a flight appendage-specific cis-regulatory element of the spalt (sal) gene. We find that multiple monomer Ubx-binding sites are required to completely repress this cis-element in the haltere, and that individual Ubx-binding sites are sufficient to mediate its partial repression. These results suggest that Hox proteins can directly regulate target genes in the absence of the cofactor Extradenticle. We propose that the regulation of some Hox target genes evolves via the accumulation of multiple Hox monomer binding sites. Furthermore, because the development and morphological diversity of the distal parts of most arthropod and vertebrate appendages involve Hox, but not Exd/Pbx or Hth/Meis proteins, this mode of target gene regulation appears to be important for distal appendage development and the evolution of appendage diversity.

egl-27 generates anteroposterior patterns of cell fusion in C. elegans by regulating Hox gene expression and Hox protein function

Development ◽  
1999 ◽  
Vol 126 (15) ◽  
pp. 3303-3312 ◽  
Author(s):  
Q. Ch'ng ◽  
C. Kenyon
Keyword(s):  
Gene Expression ◽  
Cell Fusion ◽  
Protein Function ◽  
Hox Genes ◽  
Positional Information ◽  
Cell Fates ◽  
Hox Proteins ◽  
Hox Gene ◽  
C Elegans ◽  
Hox Protein

Hox genes pattern the fates of the ventral ectodermal Pn.p cells that lie along the anteroposterior (A/P) body axis of C. elegans. In these cells, the Hox genes are expressed in sequential overlapping domains where they control the ability of each Pn.p cell to fuse with the surrounding syncytial epidermis. The activities of Hox proteins are sex-specific in this tissue, resulting in sex-specific patterns of cell fusion: in hermaphrodites, the mid-body cells remain unfused, whereas in males, alternating domains of syncytial and unfused cells develop. We have found that the gene egl-27, which encodes a C. elegans homologue of a chromatin regulatory factor, specifies these patterns by regulating both Hox gene expression and Hox protein function. In egl-27 mutants, the expression domains of Hox genes in these cells are shifted posteriorly, suggesting that egl-27 influences A/P positional information. In addition, egl-27 controls Hox protein function in the Pn.p cells in two ways: in hermaphrodites it inhibits MAB-5 activity, whereas in males it permits a combinatorial interaction between LIN-39 and MAB-5. Thus, by selectively modifying the activities of Hox proteins, egl-27 elaborates a simple Hox expression pattern into complex patterns of cell fates. Taken together, these results implicate egl-27 in the diversification of cell fates along the A/P axis and suggest that chromatin reorganization is necessary for controlling Hox gene expression and Hox protein function.

scholarly journals Hox Proteins in the Regulation of Muscle Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriela Poliacikova ◽  
Corinne Maurel-Zaffran ◽  
Yacine Graba ◽  
Andrew J. Saurin
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
Muscle Development ◽  
Hox Genes ◽  
Fruit Fly ◽  
Comprehensive Overview ◽  
Hox Proteins ◽  
Vertebrate Muscle ◽  
Hox Protein ◽  
Vertebrate Skeleton

Hox genes encode evolutionary conserved transcription factors that specify the anterior–posterior axis in all bilaterians. Being well known for their role in patterning ectoderm-derivatives, such as CNS and spinal cord, Hox protein function is also crucial in mesodermal patterning. While well described in the case of the vertebrate skeleton, much less is known about Hox functions in the development of different muscle types. In contrast to vertebrates however, studies in the fruit fly, Drosophila melanogaster, have provided precious insights into the requirement of Hox at multiple stages of the myogenic process. Here, we provide a comprehensive overview of Hox protein function in Drosophila and vertebrate muscle development, with a focus on the molecular mechanisms underlying target gene regulation in this process. Emphasizing a tight ectoderm/mesoderm cross talk for proper locomotion, we discuss shared principles between CNS and muscle lineage specification and the emerging role of Hox in neuromuscular circuit establishment.

scholarly journals Hox genes pattern the primary body axis of an anthozoan cnidarian prior to gastrulation

2017 ◽  
Author(s):  
Timothy Q. DuBuc ◽  
Thomas B. Stephenson ◽  
Amber Q. Rock ◽  
Mark Q. Martindale
Keyword(s):  
Transcription Factors ◽  
Wnt Signaling ◽  
Hox Genes ◽  
Opportunity To Learn ◽  
Sister Group ◽  
Nematostella Vectensis ◽  
Sea Anemones ◽  
Positional Identity ◽  
Primary Body ◽  
Anterior Posterior

Hox gene transcription factors are important regulators of positional identity along the anterior-posterior axis in bilaterian animals. Cnidarians (e.g. sea anemones, corals and hydroids) are the sister group to the Bilateria and possess genes related to both anterior and central/posterior class Hox genes. In the absence of a conserved set of Hox genes among other early branching animal clades, cnidarians provide the best opportunity to learn about the emergence of this gene family. We report a previously unrecognized domain of Hox expression in the starlet sea anemone, Nematostella vectensis, beginning at early blastula stages. Functional perturbation reveals that two Hox genes not only regulate their respective expression domains, but interact with one another to pattern the entire oral-aboral axis mediated by Wnt signaling. This suggests an ancient link between Hox/Wnt patterning of the oral-aboral axis and suggest that these domains are likely established during blastula formation in anthozoan cnidarians.

scholarly journals The pentapeptide motif of Hox proteins is required for cooperative DNA binding with Pbx1, physically contacts Pbx1, and enhances DNA binding by Pbx1.

1995 ◽  
Vol 15 (10) ◽  
pp. 5811-5819 ◽  
Author(s):  
P S Knoepfler ◽  
M P Kamps
Keyword(s):  
Dna Binding ◽  
Hox Genes ◽  
Mutational Analysis ◽  
Wild Type ◽  
Homeodomain Proteins ◽  
Binding Ability ◽  
Hox Proteins ◽  
Positional Identity ◽  
Methionine Residues ◽  
Anterior Posterior

The vertebrate Hox genes, which represent a subset of all homeobox genes, encode proteins that regulate anterior-posterior positional identity during embryogenesis and are cognates of the Drosophila homeodomain proteins encoded by genes composing the homeotic complex (HOM-C). Recently, we demonstrated that multiple Hox proteins bind DNA cooperatively with both Pbx1 and its oncogenic derivative, E2A-Pbx1. Here, we show that the highly conserved pentapeptide motif F/Y-P-W-M-R/K, which occurs in numerous Hox proteins and is positioned 8 to 50 amino acids N terminal to the homeodomain, is essential for cooperative DNA binding with Pbx1 and E2A-Pbx1. Point mutational analysis demonstrated that the tryptophan and methionine residues within the core of this motif were critical for cooperative DNA binding. A peptide containing the wild-type pentapeptide sequence, but not one in which phenylalanine was substituted for tryptophan, blocked the ability of Hox proteins to bind cooperatively with Pbx1 or E2A-Pbx1, suggesting that the pentapeptide itself provides at least one surface through which Hox proteins bind Pbx1. Furthermore, the same peptide, but not the mutant peptide, stimulated DNA binding by Pbx1, suggesting that interaction of Hox proteins with Pbx1 through the pentapeptide motif raises the DNA-binding ability of Pbx1.

scholarly journals Kinase Regulation of HOX Transcription Factors

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 508 ◽  
Author(s):  
Monika Primon ◽  
Keith D. Hunter ◽  
Hardev S. Pandha ◽  
Richard Morgan
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Regulation ◽  
Hox Genes ◽  
Integration Site ◽  
Cell Leukaemia ◽  
Early Event ◽  
Cell Renewal ◽  
Hox Proteins ◽  
Cycle Regulation

The HOX genes are a group of homeodomain-containing transcription factors that play important regulatory roles in early development, including the establishment of cell and tissue identity. HOX expression is generally reduced in adult cells but is frequently re-established as an early event in tumour formation and supports an oncogenic phenotype. HOX transcription factors are also involved in cell cycle regulation and DNA repair, along with normal adult physiological process including stem cell renewal. There have been extensive studies on the mechanism by which HOX proteins regulate transcription, with particular emphasis on their interaction with cofactors such as Pre-B-cell Leukaemia Homeobox (PBX) and Myeloid Ecotropic Viral Integration Site 1 (MEIS). However, significantly less is known of how the activity of HOX proteins is regulated. There is growing evidence that phosphorylation may play an important role in this context, and in this review, we draw together a number of important studies published over the last 20 years, and discuss the relevance of phosphorylation in the regulation and function of HOX proteins in development, evolution, cell cycle regulation, and cancer.

Sign in / Sign up

Export Citation Format

Share Document