Further Development 19.6: The Mechanism by which Sonic Hedgehog Establishes Digit Identity

The mechanism by which Sonic hedgehog establishes a digit’s identity may involve cell-cycle regulation and the BMP pathway. The time- and concentration-dependent actions of Shh lead to the graded activation of the downstream transcriptional effector Gli3. These targets include the genes for the BMP antagonist Gremlin, the cell cycle regulator Cdk6, and the genes that synthesize hyaluronic acid (a component of cell adhesion). Shh (through Gli3) restricts the proliferation of cartilage progenitor cells (by downregulating Cdk6) and promotes their BMP-stimulated differentiation into cartilage by inhibiting the BMP antagonist Gremlin and by upregulating hyaluronic acid synthase 2 (Vokes et al. 2008; Liu et al. 2012; Lopez-Rios et al. 2012).

Shh initiates and sustains a gradient of BMP proteins across the limb bud, and this BMP gradient can specify the digits (Laufer et al. 1994; Kawakami et al. 1996; Drossopoulou et al. 2000). Identity is not specified directly in each digit primordium, however. Rather, the identity of each digit is determined by the interdigital mesoderm—that is, by the webbing between the digits (the region of mesenchyme that will shortly undergo apoptosis).

The interdigital tissue specifies the identity of the digit forming anteriorly to it (i.e., toward the thumb or big toe). Thus, when Dahn and Fallon (2000) removed the webbing between the cartilaginous condensations forming chick hindlimb digits 2 and 3, the second digit was changed into a copy of digit 1 (Figure 1A,B). Similarly, when the webbing on the other side of digit 3 was removed, the third digit formed a copy of digit 2 (Figure 1A,C). Moreover, the positional value of the webbing could be altered by changing the BMP level (Figure 1D–F). Each digit has a characteristic array of nodules that form the digit skeleton, and Suzuki and colleagues (2008) have shown that the different levels of BMP signaling in the interdigital webbing regulate the recruitment of progress zone mesenchymal cells into the nodules that make the digits.

Figure 1 Regulation of digit identity by BMP concentrations in the interdigital space anterior to the digit and by Gli3. (A) Scheme for removal of interdigital (ID) regions. (B) Removal of ID region 2 between digit primordia 2 (p2) and 3 (p3) causes digit 2 to change to the structure of digit 1. (C) Removing ID region 3 (between digit primordia 3 and 4) causes digit 3 to form the structures of digit 2. (D) Wild-type digits and their ID spaces. (E,F) The same transformations as in (B) and (C) can be obtained by adding beads containing the BMP inhibitor Noggin to the ID regions. (E) When a Noggin-containing bead (green dot) is placed in ID region 2, digit 2 is transformed into a copy of digit 1. (F) When the Noggin bead is placed in ID region 3, digit 3 is transformed into a copy of digit 2. (After D. Dahn and J. F. Fallon. 2000. Science 289: 438–441.)

Literature Cited

Dahn, R. D. and J. F. Fallon. 2000. Interdigital regulation of digit identity and homeotic transformation by modulating BMP signaling. Science 289: 438–441.
PubMed Link

Drossopoulou, G., K. E. Lewis, J. J. Sanz-Ezguerro, N. Nikbaklt, A. P. McMahon, C. Hofman and C. Tickle. 2000. A model for anteriorposterior patterning of the vertebrate limb based on sequential long-and short-range Shh signalling and BMP signalling. Development 127: 1337–1348.
PubMed Link

Kawakami, Y., T. Ishikawa, M. Shimabara, N. Tanda, M. Enomoto-Iwamoto, M. Iwamoto, T. Kuwana, A. Ueki, S. Noji and T. Nohno. 1996. BMP signaling during bone pattern determination in the developing limb. Development 122: 3557–3566.
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Laufer, E., C. E. Nelson, R. L. Johnson, B. A. Morgan and C. Tabin. 1994. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 79: 993–1003.
PubMed Link

Liu, J. and 33 others. 2012. Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res. 22: 2315–2327.
PubMed Link

Lopez-Rios, J., D. Speziale, D. Robay, M. Scotti, M. Osterwalder, G. Nusspaumer, A. Galli, G. A. Holländer, M. Kmita and R. Zeller. 2012. GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis. Dev. Cell. 22: 837–848.
PubMed Link

Suzuki, T., S. M. Hasso and J. F. Fallon. 2008. Unique SMAD1/5/8 activity at the phalanx-forming region determines digit identity. Proc. Natl. Acad. Sci. USA 105: 4185–4190.
PubMed Link

Vokes, S. A., H. Ji, W. H. Wong and A. P. McMahon. 2008. A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev. 22: 2651–2663. 
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