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The Intersection of Genetics and Physics in Gut Development
Embryonic transformation from a simple cellular structure into complex organs involves not just genetic instruction but also the application of physical principles. Recent studies highlight the interplay between genetic mechanisms and the physical forces that shape early gut development.
Two pivotal studies published in Developmental Cell and Proceedings of the National Academy of Sciences emphasize the role of gene-controlled geometries and forces in the embryonic construction of different intestinal segments. These findings connect the dots between genetic signaling and the physical shaping of the gut during crucial developmental stages.
Decoding Gut Formation Through Hox Genes
The first study from Developmental Cell, led by Hasreet Gill, a former student in Harvard’s Griffin Graduate School of Arts and Sciences, delves into how Hox genes orchestrate gut structure. Using the chicken embryo as a model, researchers traced the gut development process, revealing that Hox genes, which are conserved across vertebrates, are instrumental in differentiating the gut’s shape and function.
“I was curious about the varying shapes of the intestine—from the esophagus to the large intestine,” stated Gill, who collaborated with her Ph.D. advisor, Clifford Tabin, a noted geneticist at Harvard Medical School. This study marks a significant stride in decoding how Hox genes direct the physical properties that influence gut morphology.
Integration of Experimental and Computational Approaches
Gill’s research utilized both experimental and computational frameworks, collaborating with Sifan Yin and L. Mahadevan to analyze how the mechanical properties of gut tissues relate to their final forms. Previous research had established Hox genes as pivotal in organ differentiation, and this study sought to uncover the specific mechanisms behind that process.
Results indicated that the distinct mechanical characteristics of the small and large intestine tissues play a critical role in shaping their structural outcomes. For instance, the stiffness of the small intestine’s villi differs markedly from that of the more expansive, flatter folds of the large intestine.
Investigating Mechanical Dynamics
To explore the implications of these mechanical variations, the research team revisited an experiment from the 1990s that demonstrated the influence of Hox genes on intestinal characteristics. Through this, they identified HoxD13 as a key regulator of the mechanical properties influencing large intestine formation, with other related Hox genes affecting the small intestine.
Moreover, they highlighted the significance of the TGF Beta signaling pathway, which Hox genes regulate. By manipulating TGF beta levels in embryonic models, the researchers could alter the shapes of various gut regions, uncovering a pathway linked to fibrosis that may also have implications for understanding conditions such as colon cancer.
“This suggests that abnormalities in gut development could be harnessed by diseases that result in excess extracellular matrix deposition,” Gill noted, indicating that insights from developmental biology could inform our understanding of such health issues.
Patterns of Growth and Morphological Changes
The complementary study published in PNAS, co-led by Gill and Yin, further explores the relationship between geometric and elastic properties in gut morphology. This research emphasizes how these factors produce distinct mechanical behaviors, including complex growth patterns observed in the gut structure.
Yin elaborated, saying, “We investigated how mechanical properties impact morphologies, particularly in terms of more intricate patterns like period-doubling and multi-scale creasing.” Mahadevan added an evolutionary perspective, posing questions about how natural genetic variations contribute to the diversity of gut forms across different species and whether environmental influences like diet play a substantial role.
The findings from these studies set the groundwork for a novel understanding of morphogenesis, as Yin concluded that morphogenesis results from the interplay of cellular activities, tissue dynamics, and environmental influences, bridging the domains of molecular biology and physical sciences.
More information:
Hasreet K. Gill et al., Hox gene activity directs physical forces to differentially shape chick small and large intestinal epithelia, Developmental Cell (2024). DOI: 10.1016/j.devcel.2024.07.012
Hasreet K. Gill et al., The developmental mechanics of divergent buckling patterns in the chick gut, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2310992121
Source
phys.org