Role of Hox genes in regulating digit patterning

Pérez-Gómez, Rocío; Haro, Endika; Fernández-Guerrero, Marc; Bastida, Maria Félix; Ros, María A.

doi:10.1387/ijdb.180200mr

Cited by 10 publications

(13 citation statements)

References 109 publications

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“…For instance, FOXC1, which is active in BCC-I, can activate SMO-independent HH signaling in basal-like breast cancer, suggesting that it may regulate BCC drug resistance ( 35 ). The HOX TFs, which are highly active in BCC-II, are main players in murine digit patterning, where HOX TFs can activate Shh transcription, with Shh protein establishing additional Hox expression zones ( 36 ). However, the interplay between HOX TFs and HH signaling in cancer is unclear.…”

Section: Resultsmentioning

confidence: 99%

Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment

et al. 2022

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How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. We use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between normal and malignant epithelial cells. We identify spatial biomarkers of tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity–PAGA, cellular entropy, and regulon analysis in stromal cells reveals a cancer-specific rewiring of fibroblasts, where STAT1, TGF-β, and inflammatory signals induce a noncanonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, whose expression we validated in situ. Last, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro vismodegib-resistant BCC cell growth, Hedgehog signaling, and in vivo tumor growth in a BCC mouse model, validating HSP70’s essential role in tumor growth and reinforcing the critical nature of tumor microenvironment cross-talk in BCC progression.

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Section: Resultsmentioning

confidence: 99%

Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment

et al. 2022

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“…Recent genetic studies have highlighted remarkable conservation and functional differences of key developmental genes in appendage diversity, including the tetrapod distal limb (prospective endochondral bones) and fish AF (prospective dermal fin rays), which are ontogenetically and structurally different. Hox transcription factors are central to body patterning in vertebrates (Deschamps & van Nes, 2005;Mallo, 2018;Young & Deschamps, 2009) and exhibit nested expression patterns in appendage primordia (Figure 2a) (Pérez-Gómez, Haro, Fernández-Guerrero, Bastida, & Ros, 2018;Zakany & Duboule, 2007). Strikingly, comparative studies in catshark (Freitas, Zhang, & Cohn, 2007), paddlefish (Davis et al, 2007;Tulenko et al, 2016), medaka (Takamatsu et al, 2007), and zebrafish (Ahn & Ho, 2008) all showed nested expression patterns of Hoxa and d genes in the endochondral disc and even in the AF, emphasizing that nested Hox expression patterns in appendage development are deeply conserved features from fins to limbs beyond their apparent morphological disparity (Davis, 2013;Lalonde & Akimenko, 2018;Tulenko et al, 2016).…”

Section: Extension Of Fin Growth and Patterningmentioning

confidence: 99%

Developmental constraints on fin diversity

et al. 2020

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The fish fin is a breathtaking repository full of evolutionary diversity, novelty, and convergence. Over 500 million years, the adaptation to novel habitats has provided landscapes of fin diversity. Although comparative anatomy of evolutionarily divergent patterns over centuries has highlighted the fundamental architectures and evolutionary trends of fins, including convergent evolution, the developmental constraints on fin evolution, which bias the evolutionary trajectories of fin morphology, largely remain elusive. Here, we review the evolutionary history, developmental mechanisms, and evolutionary underpinnings of paired fins, illuminating possible developmental constraints on fin evolution. Our compilation of anatomical and genetic knowledge of fin development sheds light on the canalized and the unpredictable aspects of fin shape in evolution. Leveraged by an arsenal of genomic and genetic tools within the working arena of spectacular fin diversity, evolutionary developmental biology embarks on the establishment of conceptual framework for developmental constraints, previously enigmatic properties of evolution.

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“…Other major regulators of digit patterning include the Hox genes, in particular, members of the HoxA and HoxD clusters (8,9). During tetrapod limb development, Hoxa genes are sequentially activated in the distal limb bud (10), but their expression evolves to generate mutually exclusive expression domains of Hoxa11 and Hoxa13.…”

mentioning

confidence: 99%

The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13

Bastida

Pérez-Gómez

Trofka

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5′Hoxd second expression phase, thereby establishing anterior−posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution.

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Role of Hox genes in regulating digit patterning

Cited by 10 publications

References 109 publications

Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment

Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment

Developmental constraints on fin diversity

The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13

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