Posted by How do you make a limb? Vertebrate limbs are classic models in organogenesis, and we know a fair bit about the molecular events involved. Limbs are induced at particular boundaries of axial Hox gene expression, and the first recognizable sign of their formation is the appearance of a thickened epithelial bump, the apical ectodermal ridge (AER). The AER is a signaling center that produces, in particular, a set of growth factors such as Fgf4 and Fgf8 that trigger the growth of the underlying tissue, causing the growing limb to protrude. In addition, there’s another signaling center that forms on the posterior side of the growing limb, and which secretes Sonic Hedgehog and defines the polarity of the limb—this center is called the Zone of Polarizing Activity, or ZPA. The activity of these two centers together define two axes of the limb, the proximo-distal and the anterior-posterior. There are other genes involved, of course—this is no simple process—but that’s a very short overview of what’s involved in the early stages of making arms and legs.
Now, gentlemen, examine your torso below the neck. You can probably count five protuberances emerging from it; my description above accounts for four of them. What about that fifth one? (Not to leave the ladies out, of course—you’ve also got the same fifth bump, it’s just not quite as obvious, and it’s usually much more tidily tucked away.)
Compared to legs and arms, of course, that fifth bump isn’t much, even in the guys. Early in development, though, it’s much more impressive in relative scale. Here is a crotch shot of a mouse embryo; the paddle-like things on either side are the hindlimbs, and the thick fireplug of a protuberance in the middle, looking like something Vaughn Bode would have drawn, is the genital tubercle…and at these early stages, it would look pretty much the same in a male or female mouse.
A: SEM photo of an embryonic GT and hindlimbs at E12.0. Arrow: Distal urethral epithelium (DUE) and urethral plate; Arrowheads: apical ectodermal
ridge (AER) in hindlimb. The embryonic tail region was removed.
In this paper by Yamada et al., the investigators examined the patterns of gene expression in that developing genital tubercle, and the place to start, obviously enough, was to use probes against genes that were known to be important in the development of those other four protuberances: genes like the Fgfs, Shh, and other known components of signalling cascades, like Wnt5a and Bmp genes. I trust you won’t be too surprised to learn that there’s quite a bit of correspondence.
Expression patterns of several genes (Fgf8, Shh, Wnt5a, Bmp4, Bmp7) during mouse genital tubercle (GT; B-F) and limb development (G-K). Whole-mount in situ hybridization with digoxigenin-labeled Fgf8, Shh, Wnt5a, Bmp4,
and Bmp7 probes. B-F: Murine embryonic GT at E12.5. Lower (ventral) side of GT is shown. G-J: Embryonic limb at E11.5. K: Murine embryonic limb
at E10.5. Note the “similar” expression of Fgf8 and Wnt5a in the distal epithelia and distal mesenchyme of limbs and GT. Shh is expressed in the
urethral plate (UP) (C) and in ZPA (H). Bmp4 is expressed in ventral-distal mesenchyme and ventral bilateral mesenchyme close to the urethral plate
(E). Bmp4 is expressed in limb mesenchyme (J). Bmp7 is expressed in the DUE (F) and also in AER of limbs (K).
Similar signaling cascades are being used in the assembly of both the limb and the genital tubercle—there’s Wnt5a/Fgf center at the tip, and a site for secretion of Shh localized to the posterior edge. There are also major differences, of course. One significant structural difference between a limb and a penis is that a penis contains a central duct, the urethra, and this has to form by folding of an epithelial sheet. Still, you can see a core developmental module in place in both kinds of structures, with a distal growth center using Wnts and Fgfs and Bmps, and a posterior polarizing center that uses Shh.
Signaling cascades for genital tubercle (GT) formation (A) and for limb formation (B). DUE,
the signaling epithelia of the GT, expresses Fgf8 and Bmp7. Adjacent to DUE, the distal mesenchyme of the GT expresses Bmp4 and Wnt5a. In the GT, the urethral plate expresses Shh in the
ventral midline (red region in A). Bilateral to the urethral plate, Fgf10 is expressed (C). AER is located
in the distal tip of the developing limb (B) and it expresses Fgf8, Fgf9, and Fgf4. Shh is expressed
in ZPA of the posterior limb and Wnt5a is expressed in the distal mesenchyme of limb (B). In the
GT, midline Shh is expressed adjacent to the bilateral mesenchyme, which expresses Fgf10 (D, E).
Shh (D) and Fgf10 (E) gene expression in the E13.5 embryonic mouse GT.
As additional evidence for some kind of coupling between the molecules of the limbs and genitals, the authors cite a number of rare genetic syndromes that share simultaneous defects in limbs and genitals, such as hand-foot-genital syndrome, Robinow syndrome, Pallister-Hall syndrome, and so on (not all of which I find convincing—they have such a broad distribution of effects that tying genital and limb formation together is difficult.)
Seeing these similarities is not a surprising result at all. Evolution reuses what it can; it’s far easier to develop a novel protuberance by switching on an existing ‘protuberance pathway’ in a new place than to generate entirely new molecular mechanisms to do the same thing. Both limbs and mammalian genitals bulge outward, and at least in that superficial element of their organization, it’s interesting to see that the same molecules are involved. What’s also fascinating is that they also have major differences, and sorting out the causal mechanisms behind the variations imposed on the root homologies is going to be extremely informative.
Unfortunately, the paper didn’t address the really pressing question: if limb and genital development are coupled to some degree, is it true what they say about shoe size?
Goodman FR,
Bacchelli C,
Brady AF,
Brueton LA,
Fryns JP,
Mortlock DP,
Innis JW,
Holmes LB,
Donnenfeld AE,
Feingold M,
Beemer FA,
Hennekam RC,
Scambler PJ (2000) Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am J Hum Genet. 67(1):197-202.
Yamada G, Suzuki K, Haraguchi R, Miyagawa S, Satoh Y, Kamimura M, Nakagata N, Kataoka H, Kuroiwa A, Chen Y (2006) Molecular genetic cascades for external genitalia formation: an emerging organogenesis program. Dev Dyn 235(7):1738-52.
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