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

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.

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

Development ◽

10.1242/dev.193813 ◽

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.

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Regulation of Pax-3 expression in the dermomyotome and its role in muscle development

Development ◽

10.1242/dev.120.4.957 ◽

1994 ◽

Vol 120 (4) ◽

pp. 957-971 ◽

Cited By ~ 63

Author(s):

M. Goulding ◽

A. Lumsden ◽

A.J. Paquette

Keyword(s):

Transcription Factors ◽

Muscle Development ◽

Cell Types ◽

Axial Skeleton ◽

Mouse Embryos ◽

Related Gene ◽

Paired Domain ◽

Trunk Musculature ◽

Somitic Mesoderm

The segmented mesoderm in vertebrates gives rise to a variety of cell types in the embryo including the axial skeleton and muscle. A number of transcription factors containing a paired domain (Pax proteins) are expressed in the segmented mesoderm during embryogenesis. These include Pax-3 and a closely related gene, Pax-7, both of which are expressed in the segmental plate and in the dermomyotome. In this paper, we show that signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and the subsequent differentiation of cell types that arise from the somitic mesoderm. We directly assess the role of the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing the development of muscle in splotch mouse embryos which lack a functional Pax-3 gene. A population of Pax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent in homozygous splotch embryos and, as a result, limb muscles are lost. No abnormalities were detected in the trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of the limb but not trunk muscle.

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

Development ◽

10.1242/dev.125.7.1269 ◽

1998 ◽

Vol 125 (7) ◽

pp. 1269-1274 ◽

Cited By ~ 2

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.

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Some Questions and Answers About the Role of Hox Temporal Collinearity in Vertebrate Axial Patterning

10.20944/preprints201909.0192.v1 ◽

2019 ◽

Author(s):

A.J.Durston Durston

Keyword(s):

Axial Patterning ◽

Common Features ◽

Timing Mechanism ◽

Questions And Answers ◽

Competing Models ◽

Anterior Posterior

The vertebrate anterior-posterior (A-P = craniocaudal) axis is evidently made by a timing mechanism. Evidence has accumulated that tentatively identifies the A-P timer as being or involving Hox temporal collinearity. Here, I focus on the two current competing models based on this premise. Common features and points of dissent are examined and a common model is distilled from what remains. This is an attempt to make sense of the literature.

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Lysine demethylase 7a regulates the anterior-posterior development in mouse by modulating the transcription of Hox gene cluster

10.1101/707125 ◽

2019 ◽

Author(s):

Yoshiki Higashijima ◽

Nao Nagai ◽

Taro Kitazawa ◽

Yumiko Kawamura ◽

Akashi Taguchi ◽

...

Keyword(s):

Transcriptional Activation ◽

Axial Skeleton ◽

Regulatory Mechanisms ◽

Vertebrate Development ◽

Post Translational Modifications ◽

Body Patterning ◽

Temporal And Spatial ◽

Lysine Demethylase ◽

Anterior Posterior

SUMMARYTemporal and spatial colinear expression of the Hox genes determines the specification of positional identities during vertebrate development. Post-translational modifications of histones contribute to transcriptional regulation. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 di-methylation of histone H3 (H3K9me2) and participates in the transcriptional activation of developmental genes. However, the role of Kdm7a during mouse embryonic development remains to be elucidated. Here, we show that Kdm7a−/− mouse exhibits an anterior homeotic transformation of the axial skeleton, including an increased number of presacral elements. Importantly, posterior Hox genes (caudally from Hox9) are specifically downregulated in the Kdm7a−/− embryo, which correlates with increased levels of H3K9me2. These observations suggest that Kdm7a controls the transcription of posterior Hox genes, likely via its demethylating activity, and thereby regulating the murine anterior-posterior development. Such epigenetic regulatory mechanisms may be harnessed for the proper control of coordinate body patterning in vertebrates.

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The role of Zic transcription factors in regulating hindbrain retinoic acid signaling

BMC Developmental Biology ◽

10.1186/1471-213x-13-31 ◽

2013 ◽

Vol 13 (1) ◽

pp. 31 ◽

Cited By ~ 13

Author(s):

Danna L Drummond ◽

Caroline S Cheng ◽

Lyndsay G Selland ◽

Jennifer C Hocking ◽

Lisa B Prichard ◽

...

Keyword(s):

Transcription Factors ◽

Retinoic Acid ◽

Retinoic Acid Signaling

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Lysine demethylase 7a regulates murine anterior-posterior development by modulating the transcription of Hox gene cluster

Communications Biology ◽

10.1038/s42003-020-01456-5 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Yoshiki Higashijima ◽

Nao Nagai ◽

Masamichi Yamamoto ◽

Taro Kitazawa ◽

Yumiko K. Kawamura ◽

...

Keyword(s):

Transcriptional Activation ◽

Axial Skeleton ◽

Regulatory Mechanisms ◽

Vertebrate Development ◽

Post Translational Modifications ◽

Body Patterning ◽

Temporal And Spatial ◽

Lysine Demethylase ◽

Anterior Posterior

AbstractTemporal and spatial colinear expression of the Hox genes determines the specification of positional identities during vertebrate development. Post-translational modifications of histones contribute to transcriptional regulation. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 or 27 di-methylation of histone H3 (H3K9me2, H3K27me2) and participates in the transcriptional activation of developmental genes. However, the role of Kdm7a during mouse embryonic development remains to be elucidated. Herein, we show that Kdm7a−/− mouse exhibits an anterior homeotic transformation of the axial skeleton, including an increased number of presacral elements. Importantly, posterior Hox genes (caudally from Hox9) are specifically downregulated in the Kdm7a−/− embryo, which correlates with increased levels of H3K9me2, not H3K27me2. These observations suggest that Kdm7a controls the transcription of posterior Hox genes, likely via its demethylating activity, and thereby regulating the murine anterior-posterior development. Such epigenetic regulatory mechanisms may be harnessed for proper control of coordinate body patterning in vertebrates.

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Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors

Nature Communications ◽

10.1038/s41467-021-23373-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Irene Delgado ◽

Giovanna Giovinazzo ◽

Susana Temiño ◽

Yves Gauthier ◽

Aurelio Balsalobre ◽

...

Keyword(s):

Transcription Factors ◽

Limb Development ◽

Critical Factor ◽

Interaction Networks ◽

Lateral Plate Mesoderm ◽

Lateral Plate ◽

Hox Proteins ◽

Mouse Limb ◽

Limb Initiation

AbstractMeis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1/2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis.

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