上肢や下肢が出る位置はどのようにして決まるのか？

上肢や下肢が出る位置はどのようにして決まるのでしょうか？体軸の位置はHOXコードで決まるのだとすれば、ある特定のHOX遺伝子産物が転写制御因子となって上肢や下肢の肢芽で発現するTbx5やTbx4の発現を直接制御するのでしょうか（エンハンサーかプロモーターに特異的に結合するなどして）？

下の総説によれば、HOX遺伝子が活性化や抑制に働くようです。

A Combination of Activation and Repression by a Colinear Hox Code Controls Forelimb-Restricted Expression of Tbx5 and Reveals Hox Protein Specificity Satoko Nishimoto,Carolina Minguillon,Sophie Wood,Malcolm P. O. Logan Published: March 20, 2014 https://doi.org/10.1371/journal.pgen.1004245

最近の総説論文を読むと, HOXコードで前肢の出る位置は決まるようですが、そう単純ではなさそうです。ただTbx5はFgf10遺伝子のプロモーターに直接結合して発現を誘導するそうです。下肢については、前肢ほどには研究がなされておらず、HOXコードで位置が規定されるのか、FGF10を発現させるものが何なのかについては報告がなさそうです。

  1. Current research on mechanisms of limb bud development, and challenges for the next decade Takayuki Suzuki　Genes & Genetic Systems/Volume 99 (2024)　https://www.jstage.jst.go.jp/article/ggs/99/0/99_23-00287/_html/-char/en　

 

  1. Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo　Development (2003) 130 (3): 623–633.　https://journals.biologists.com/dev/article/130/3/623/42069/Tbx5-is-essential-for-forelimb-bud-initiation
    1. mouse embryos lacking Tbx5 do not form forelimb buds
    2. Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation
  2. Tbx5 is required for forelimb bud formation and continued outgrowth　Development . 2003 Jun;130(12):2741-51. doi: 10.1242/dev.00473.

Fig. 3. Antero-posterior limb polarity. (A) Major regulatory interactions involved in the specification of forelimb field antero-posterior polarity. Retinoic acid (RA) signalling is implicated in the defined anterior to posterior order of expression of Hox5-Hox9 paralogous group (PG) genes in presumptive forelimb regions of the lateral plate mesoderm (LPM). Hox5 PG proteins repress anterior Shh expression indirectly through activation of Plzf. Gata4 and Gata6 proteins transcriptionally inhibit Shh and attenuate Shh signal transduction by promoting the repressor form of Gli3. RA stimulates the posterior expression of Hand2, the product of which both represses Gli3 in the posterior part of the limb bud and stimulates Shh expression at the posterior margin. Gli3 also represses Hand2. Sall4 is expressed in the presumptive forelimb and its protein product contributes to the expression of Gli3. (B) Major regulatory interactions involved in the specification of hindlimb field antero-posterior polarity. Gata6 directly represses anterior expression of Shh. Sall4, Irx3 and Irx5 regulate Gli3 expression anteriorly. Isl1 indirectly promotes the posterior expression of Shh in the hindlimb by inducing Hand2, which represses Gli3 in the posterior part of the hindlimb. A, anterior; P, posterior.

https://journals.biologists.com/dev/article/147/17/dev177956/225797/Establishing-the-pattern-of-the-vertebrate-limb