Morphogen gradient interpretation and Sonic Hedgehog signalling
A morphogen gradient is a spatial variation in a signalling molecule that cells can use to learn their position and choose a fate. Sonic Hedgehog (Shh) is one gradient examined in work on the neural tube. Work on the neural tube argues that a transcriptional circuit, not concentration alone, does the reading4. The question stays open, because it is not known what feature of a gradient organisms read6.
- Earliest held
- 1915, Child, C. M.
- Most discussed in
- Gene regulatory logic for reading the Sonic…, 2012
- In the library
- 74 passages in 18 works
- Rewritten
- 2026-10-25
Early gradient ideas
Child (1915), in Individuality in Organisms, described morphogenic gradients as belonging not only to the minor axes of the whole body but also to the axes of particular organs or parts1. His figures of frog egg cleavage showed a gradient in cell size that resulted from a gradient in the rate of division1. In this view the law of antero-posterior development is one statement, for the major axis, of a more general law of axial developmental gradients.
Positional information and its limits
Grodstein, McMillen and Levin (2023) summarise the positional-information hypothesis of Wolpert (1969). A morphogen gradient forms by an unspecified process, and cells use a gene regulatory network to sample it, infer position and differentiate2. They note two problems. The hypothesis never explained where the initial gradient came from. Most gradients also decay exponentially, so much of the field holds very low concentrations, which makes position hard to read there3. They add that it is not known whether organisms read concentration, its slope, or a fold-change between neighbouring cells6.
Shh in the neural tube
Balaskas and colleagues (2012) used an in vivo reporter of Gli activity to follow Shh signalling in the neural tube. With in silico and in vivo evidence, they argued that the regulatory logic of a Pax6, Olig2 and Nkx2.2 circuit interprets the gradient4. In their account the circuit explains both the temporal and the graded response. The circuit appears to render cells insensitive to transient increases in Shh and produces hysteresis, which gives cells a memory of the signal4. Embryos given a Smo agonist, which bypasses Ptch1-mediated negative feedback, still showed falling signalling after an initial burst. The authors concluded that cell autonomous feedback contributes to the temporal adaptation of Gli activity5.
Bioelectric and collective readings
Silic and Zhang (2023) review reports that bioelectricity touches Hedgehog signalling. In NIH-3T3 cells, PTCH1 acts as a potassium-powered cholesterol transporter that antagonises SMO. Another report found that PTCH1 inhibition of SMO depends on extracellular sodium. They suggest bioelectricity may act at both secretion and reception of Shh7. McMillen and Levin (2024) argue that in planaria the bioelectric state and downstream gradients are interpreted by collectives of cells, not single cells9. In the simulations of Palacios and colleagues (2020), morphogen gradients could be interpreted as beliefs about the role that each cell must have, at the ensemble level8.
morphogenic gradients appear in relation not only to the minor axes of the whole body, but also in relation to the axes of particular organs or parts.
Child, C. M., 1915 · Individuality in Organisms · open at passage 121it appears to render cells insensitive to transient increases in Shh signaling and produces hysteresis, providing cells with a memory of the signal.
Balaskas N, Ribeiro A, Panovska J, Dessaud E, Sasai N, Page…, 2012 · Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the… · open at passage 4Taken together, therefore, the data support the idea that cell autonomous feedback contributes to the temporal adaptation of Gli activity.
Balaskas N, Ribeiro A, Panovska J, Dessaud E, Sasai N, Page…, 2012 · Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the… · open at passage 27Notably, in our simulations, morphogen gradients could be interpreted as the expression of beliefs about the possible role at the ensemble level that each cell or element at the level below must have.
Palacios ER, Razi A, Parr T, Kirchhoff M, Friston K, 2020 · On Markov blankets and hierarchical self-organisation · open at passage 62First, some unspecified process creates a gradient of a morphogen from, say, head to tail. Next, cells use a gene regulatory network (GRN) to determine their position by sampling the morphogen gradient, and then differentiate accordingly.
Grodstein J, McMillen P, Levin M, 2023 · Closing the loop on morphogenesis: a mathematical model of morphogenesis by… · open at passage 5But it never per se explained where the initial gradient came from. Furthermore, most morphogen gradients exhibit exponential decay, which implies that much of the field will contain very low concentrations.
Grodstein J, McMillen P, Levin M, 2023 · Closing the loop on morphogenesis: a mathematical model of morphogenesis by… · open at passage 5Furthermore, it is not known whether organisms read the morphogen concentration, its concentration gradient, a fold-change between neighboring cells, or something else
Grodstein J, McMillen P, Levin M, 2023 · Closing the loop on morphogenesis: a mathematical model of morphogenesis by… · open at passage 78Thus, bioelectricity may modulate multiple steps of hedgehog signaling from SHH secretion (establishment of morphogen gradients) to SHH reception (interpretation of morphogen)
Silic MR, Zhang G, 2023 · Bioelectricity in Developmental Patterning and Size Control: Evidence and… · open at passage 51the randomization of bioelectric state131,132 and the downstream morphogen gradients is interpreted with respect to anterior-posterior organ identity by collectives, not by individual cells.
McMillen P, Levin M, 2024 · Collective intelligence: A unifying concept for integrating biology across… · open at passage 17