Limb Bud - Relevant Molecules

Relevant Molecules

• FGF10 = Initially, Tbx proteins induce secretion of FGF10 by cells in the lateral plate mesoderm. Later, FGF10 expression is restricted to the developing limb mesenchyme, where it is stabilized by WNT8C or WNT2B. FGF10 expression activates secretion of WNT3A, which acts upon the apical ectodermal ridge (AER) and induces FGF8 expression. The mesenchyme, through FGF10 secretion, is involved in a positive feedback loop with the AER, through FGF8 secretion.

• FGF8 = Secreted by the apical ectodermal ridge cells. Acts upon the mesenchyme cells, to maintain their proliferative state. Also induces the mesenchymal cells to secrete FGF10, which acts through WNT3A to sustain the AER’s expression of FGF8.

• WNT3A = Acts as a middle man in the positive feedback loop between the AER and limb mesenchyme. Activated by FGF10 expression, activates FGF8 expression.

• Shh = Secreted by the ZPA in the limb bud mesenchyme. Creates concentration gradient that dictates formation of the five distinct digits. Digit 5 (pinkie) results from exposure to high Shh concentrations, while digit 1 (thumb) on the opposite end of the spectrum develops in response to low concentrations of Shh. Shh expression has been shown in many, but not all circumstances, to be heavily connected with Hox gene expression. Shh also (via Gremlin) blocks bone morphogenic protein (BMP) activity. By blocking BMP activity, FGF expression in the AER is maintained.

• Tbx4/5 = Involved with the development of hindlimbs versus forelimbs. Though in chicks, they seem to be the primary factors involved in limb identity, in mice it appears that Tbx4 is merely a downstream messenger enforcing the hindlimb-forming instructions of Pitx1. Whether Pitx1 merely diverts a prospective forelimb from that path to become a hindlimb, or if Tbx5 is activated by another Pitx1-like messenger, is unknown.

• Pitx1 = Responsible for the development of a hindlimb-associated phenotype. Tbx4 is one of its downstream targets

• Hox genes = Responsible for dictating the anterior-posterior axis of an organism, and Is intricately involved in patterning of the developing limb in conjunction with Shh. Infuences the activity of TBX and FGF (and possibly Pitx1) proteins. Determines where limb buds will form, and what limbs will develop there.