Decision letter: Lin28a/let-7 pathway modulates the Hox code via Polycomb regulation during axial patterning in vertebrates

AbstractThe body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of Hox genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of Hox genes are not fully understood. In this study, we demonstrated that the Lin28a/let-7 reciprocal regulatory pathway is critical for vertebral specification. Lin28a−/− mice exhibited homeotic transformations of vertebrae which were caused by the global dysregulation of posterior Hox genes. The accumulation of let-7-family microRNAs in Lin28a−/− mice resulted in the reduction of PRC1 occupancy at the Hox cluster loci by targeting Cbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior Hox genes, which was rescued by the knockdown of let-7-family microRNAs. These results suggest that Lin28/let-7 pathway is possibly involved in the modulation of the “Hox code” via Polycomb regulation during axial patterning in vertebrates.

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Lin28a/let-7 pathway modulates the Hox code via Polycomb regulation during axial patterning in vertebrates

eLife ◽

10.7554/elife.53608 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Tempei Sato ◽

Kensuke Kataoka ◽

Yoshiaki Ito ◽

Shigetoshi Yokoyama ◽

Masafumi Inui ◽

...

Keyword(s):

Molecular Mechanisms ◽

Hox Genes ◽

Expression Patterns ◽

Embryonic Stem ◽

The Body ◽

Tight Control ◽

Tail Bud ◽

Axial Patterning ◽

Spatiotemporal Expression ◽

Hox Code

The body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of Hox genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of Hox genes are not fully understood. In this study, we demonstrated that the Lin28a/let-7 pathway is critical for axial elongation. Lin28a–/– mice exhibited axial shortening with mild skeletal transformations of vertebrae, which were consistent with results in mice with tail bud-specific mutants of Lin28a. The accumulation of let-7 in Lin28a–/– mice resulted in the reduction of PRC1 occupancy at the Hox cluster loci by targeting Cbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior Hox genes, which was rescued by the knockdown of let-7. These results suggest that the Lin28/let-7 pathway is involved in the modulation of the ‘Hox code’ via Polycomb regulation during axial patterning.

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Axial patterning in snakes and caecilians: Evidence for an alternative interpretation of the Hox code

Developmental Biology ◽

10.1016/j.ydbio.2009.04.031 ◽

2009 ◽

Vol 332 (1) ◽

pp. 82-89 ◽

Cited By ~ 80

Author(s):

Joost M. Woltering ◽

Freek J. Vonk ◽

Hendrik Müller ◽

Nabila Bardine ◽

Ioana L. Tuduce ◽

...

Keyword(s):

Alternative Interpretation ◽

Axial Patterning ◽

Hox Code

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Faculty Opinions recommendation of A role for MKP3 in axial patterning of the zebrafish embryo.

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

10.3410/f.1019417.220518 ◽

2004 ◽

Author(s):

Ben Zion Shilo

Keyword(s):

Zebrafish Embryo ◽

Axial Patterning

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Neuroendocrine prostate cancer has distinctive, non-prostatic HOX code that is represented by the loss of HOXB13 expression

Scientific Reports ◽

10.1038/s41598-021-82472-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Siyuan Cheng ◽

Shu Yang ◽

Yingli Shi ◽

Runhua Shi ◽

Yunshin Yeh ◽

...

Keyword(s):

Prostate Cancer ◽

Hox Genes ◽

Human Cancer ◽

Specific Expression ◽

Hox Gene ◽

Human Cancer Cell Lines ◽

All Trans Retinoic Acid ◽

Neuroendocrine Prostate Cancer ◽

Hox Code ◽

Specific Expression Pattern

AbstractHOX gene-encoded homeobox proteins control body patterning during embryonic development; the specific expression pattern of HOX genes may correspond to tissue identity. In this study, using RNAseq data of 1019 human cancer cell lines that originated from 24 different anatomic sites, we established HOX codes for various types of tissues. We applied these HOX codes to the transcriptomic profiles of prostate cancer (PCa) samples and found that the majority of prostate adenocarcinoma (AdPCa) samples sustained a prostate-specific HOX code whereas the majority of neuroendocrine prostate cancer (NEPCa) samples did not, which reflects the anaplastic nature of NEPCa. Also, our analysis showed that the NEPCa samples did not correlate well with the HOX codes of any other tissue types, indicating that NEPCa tumors lose their prostate identities but do not gain new tissue identities. Additionally, using immunohistochemical staining, we evaluated the prostatic expression of HOXB13, the most prominently changed HOX gene in NEPCa. We found that HOXB13 was expressed in both benign prostatic tissues and AdPCa but its expression was reduced or lost in NEPCa. Furthermore, we treated PCa cells with all trans retinoic acid (ATRA) and found that the reduced HOXB13 expression can be reverted. This suggests that ATRA is a potential therapeutic agent for the treatment of NEPCa tumors by reversing them to a more treatable AdPCa.

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Homeobox genes and axial patterning

Cell ◽

10.1016/0092-8674(92)90471-n ◽

1992 ◽

Vol 68 (2) ◽

pp. 283-302 ◽

Cited By ~ 1600

Author(s):

William McGinnis ◽

Robb Krumlauf

Keyword(s):

Homeobox Genes ◽

Axial Patterning

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The origins of primitive blood in Xenopus: implications for axial patterning

Development ◽

10.1242/dev.126.3.423 ◽

1999 ◽

Vol 126 (3) ◽

pp. 423-434 ◽

Cited By ~ 4

Author(s):

M.C. Lane ◽

W.C. Smith

Keyword(s):

Xenopus Laevis ◽

Marginal Zone ◽

Cell Stage ◽

Axial Patterning ◽

Xenopus Embryos ◽

Spemann's Organizer ◽

Dorsal Mesoderm

The marginal zone in Xenopus laevis is proposed to be patterned with dorsal mesoderm situated near the upper blastoporal lip and ventral mesoderm near the lower blastoporal lip. We determined the origins of the ventralmost mesoderm, primitive blood, and show it arises from all vegetal blastomeres at the 32-cell stage, including blastomere C1, a progenitor of Spemann's organizer. This demonstrates that cells located at the upper blastoporal lip become ventral mesoderm, not solely dorsal mesoderm as previously believed. Reassessment of extant fate maps shows dorsal mesoderm and dorsal endoderm descend from the animal region of the marginal zone, whereas ventral mesoderm descends from the vegetal region of the marginal zone, and ventral endoderm descends from cells located vegetal of the bottle cells. Thus, the orientation of the dorsal-ventral axis of the mesoderm and endoderm is rotated 90(degrees) from its current portrayal in fate maps. This reassessment leads us to propose revisions in the nomenclature of the marginal zone and the orientation of the axes in pre-gastrula Xenopus embryos.

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GSK3beta/shaggy mediates patterning along the animal-vegetal axis of the sea urchin embryo

Development ◽

10.1242/dev.125.13.2489 ◽

1998 ◽

Vol 125 (13) ◽

pp. 2489-2498 ◽

Cited By ~ 19

Author(s):

F. Emily-Fenouil ◽

C. Ghiglione ◽

G. Lhomond ◽

T. Lepage ◽

C. Gache

Keyword(s):

Sea Urchin ◽

Wnt Pathway ◽

Dominant Negative ◽

Early Gene ◽

Expression Domain ◽

Animal Pole ◽

Axial Patterning ◽

Sea Urchin Embryo ◽

Vegetal Pole ◽

Dominant Negative Activity

In the sea urchin embryo, the animal-vegetal axis is defined before fertilization and different embryonic territories are established along this axis by mechanisms which are largely unknown. Significantly, the boundaries of these territories can be shifted by treatment with various reagents including zinc and lithium. We have isolated and characterized a sea urchin homolog of GSK3beta/shaggy, a lithium-sensitive kinase which is a component of the Wnt pathway and known to be involved in axial patterning in other embryos including Xenopus. The effects of overexpressing the normal and mutant forms of GSK3beta derived either from sea urchin or Xenopus were analyzed by observation of the morphology of 48 hour embryos (pluteus stage) and by monitoring spatial expression of the hatching enzyme (HE) gene, a very early gene whose expression is restricted to an animal domain with a sharp border roughly coinciding with the future ectoderm / endoderm boundary. Inactive forms of GSK3beta predicted to have a dominant-negative activity, vegetalized the embryo and decreased the size of the HE expression domain, apparently by shifting the boundary towards the animal pole. These effects are similar to, but even stronger than, those of lithium. Conversely, overexpression of wild-type GSK3beta animalized the embryo and caused the HE domain to enlarge towards the vegetal pole. Unlike zinc treatment, GSK3beta overexpression thus appeared to provoke a true animalization, through extension of the presumptive ectoderm territory. These results indicate that in sea urchin embryos the level of GSKbeta activity controls the position of the boundary between the presumptive ectoderm and endoderm territories and thus, the relative extent of these tissue layers in late embryos. GSK3beta and probably other downstream components of the Wnt pathway thus mediate patterning both along the primary AV axis of the sea urchin embryo and along the dorsal-ventral axis in Xenopus, suggesting a conserved basis for axial patterning between invertebrate and vertebrate in deuterostomes.

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