Morphogen gradient interpretation, Shh signalling and adaptation
A morphogen gradient is a spread of signal across tissue that cells read to choose a fate. In the vertebrate neural tube, Sonic Hedgehog (Shh) forms such a gradient and sorts ventral progenitors into distinct domains.3 Cells respond to dose and to duration, and they appear to adapt to continued exposure.4 How cells read gradients in general is still not settled.9
- Earliest held
- 1915, Child, C. M.
- Most discussed in
- Gene regulatory logic for reading the Sonic…, 2012
- In the library
- 85 passages in 32 works
- Rewritten
- 2026-10-25
Early gradient ideas
Child (1915) described developmental gradients as a general law. He wrote that morphogenic gradients appear in relation to the axes of particular organs and parts, as well as to the minor axes of the whole body.1 His example was the frog egg, where a gradient in the rate of division produced a gradient in cell size.1 Lillie (1923) used the word desensitization in a different setting. He reported that exposing muscle to calcium or magnesium salts lowered its susceptibility to chemical stimulation. He grouped this with narcosis and anaesthesia, and noted that Ringer's solution reversed it.2
Reading Shh in the neural tube
Balaskas and colleagues (2012) summarised the neural tube case. Shh comes from the notochord and floor plate and divides the ventral neuroepithelium into five progenitor domains. In vitro, higher Shh concentrations or higher Gli activity, the intracellular effectors of Shh, induce more ventral fates.3 Identity also depends on duration, since more ventral fates need longer signalling. Cells appear to adapt to ongoing Shh by becoming desensitized to it.4
Feedback and its limits
Balaskas and colleagues examined the role of Ptch1, a negative regulator of the pathway. Ptch1 transcript and protein rise in a pattern that matches Gli activity, and the Shh gradient grows in amplitude when feedback is absent.5 In the Drosophila wing disc, Ptch upregulation has been proposed to sequester Hh and limit its spread. The authors judged this unlikely to be the main mechanism here. The Shh gradient increases in amplitude and range while Ptch1 and Gli activity gradients fall.5
Memory and open questions
Baluška and Levin (2016) called desensitization one kind of basic memory element. They noted drug addiction reactions in cultured mammalian cells. They say this suggests this form of memory is not always a body-level phenomenon that necessarily involves the brain.6 Herrera-Delgado and colleagues (2018) modelled the neural tube network and found it multistable. Different combinations of steady states are available at different positions along the Shh gradient.7 Grodstein, McMillen and Levin (2023) noted that positional information never explained the origin of the gradient. Most morphogen gradients decay exponentially, which leaves much of the field at very low concentration and makes position hard to read.8 They add that it is unknown whether organisms read concentration, slope or fold-change.9
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 121Such desensitizing effects are closely related to those classed under narcosis, depression, or anaesthesia, and are also reversible in Ringer's solution.
Lillie, R. S., 1923 · Protoplasmic Action and Nervous Action · open at passage 611increasing concentrations of Shh ligand or increasing levels of Gli activity, the intracellular transcriptional effectors of Shh signaling, induce successively more ventral neural fates
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 2In vitro studies suggest that cells respond to ongoing exposure to Shh through an adaptation mechanism in which cells become desensitized to Shh
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 2This mechanism is unlikely to play the major role in the dynamics of Gli activity in the neural tube because the amplitude and range of the Shh gradient increase during the period of time that the Ptch1 and Gli activity gradients decrease
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 26The increased tolerance with exposure is desensitization (one kind of basic memory element).
Baluška F, Levin M, 2016 · On Having No Head: Cognition throughout Biological Systems · open at passage 25the system is multistable (Fig 3E) and different combinations of steady states are available at different positions along the dorsal ventral axis (Shh gradient)
Herrera-Delgado E, Perez-Carrasco R, Briscoe J, Sollich P, 2018 · Memory functions reveal structural properties of gene regulatory networks · open at passage 60most 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 5it 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 78