A Dual Role for Hox Genes in Limb Anterior-Posterior Asymmetry

Abstract

Anterior-to-posterior patterning, the process whereby our digits are differently shaped, is a key aspect of limb development. It depends on the localized expression in posterior limb bud of Sonic hedgehog (Shh) and the morphogenetic potential of its diffusing product. By using an inversion of and a large deficiency in the mouse HoxD cluster, we found that a perturbation in the early collinear expression of Hoxd11, Hoxd12, and Hoxd13 in limb buds led to a loss of asymmetry. Ectopic Hox gene expression triggered abnormal Shh transcription, which in turn induced symmetrical expression of Hox genes in digits, thereby generating double posterior limbs. We conclude that early posterior restriction of Hox gene products sets up an anterior-posterior prepattern, which determines the localized activation of Shh. This signal is subsequently translated into digit morphological asymmetry by promoting the late expression of Hoxd genes, two collinear processes relying on opposite genomic topographies, upstream and downstream Shh signaling.

Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics

“…Noticeably, ectopic expression of Shh in this context leads to respecification of digits along the AP axis, but not to polydactyly. This finding may relate to a requirement of Hoxd genes for proper growth of the appendages (Zakany et al, 2004).…”

“…4) are initially expressed over the whole limb bud, whereas Hoxd10-Hoxd13 are expressed in a posteriorly restricted domain from the onset of their expression (Nelson et al, 1996;Zakany et al, 2004). This early pattern is Shh-independent (Grieshammer et al, 1996;Ros et al, 1996;Neumann et al, 1999;Kraus et al, 2001;Ros et al, 2003).…”

“…This early pattern is Shh-independent (Grieshammer et al, 1996;Ros et al, 1996;Neumann et al, 1999;Kraus et al, 2001;Ros et al, 2003). By inducing an inversion of the whole HoxD cluster, Zakany et al (2004) observed an ectopic expression of Hoxd11 and Hoxd13 over the entire limb bud, including the anterior domain, at early stages. The same result was obtained with a large deletion that eliminates Hoxd1-Hoxd10 and brings Hoxd11 at the 3Ј end of the cluster.…”

“…4A). In turn, Hoxd10-Hoxd13 genes may activate Shh (Zakany et al, 2004). The 5Ј regulatory region, thus, would be responsible for the precise localization of Shh transcripts.…”

Evolution of vertebrate appendicular structures: Insight from genetic and palaeontological data

“…4). Temporal collinearity and progressive restriction of Hoxd gene transcripts towards the posterior of early limb bud is employed by two distinct poorly defined cis-regulatory modules positioned telomeric (Early limb control regulation, ELCR) and centromeric (Posterior restriction, POST) to the Hoxd cluster (Zakany et al, 2004;. ELCR induce transcription in a time-dependent manner, i.e., the closer the gene is located to ELCR, the earlier its expression is induced, whereas the POST impose spatial restriction on 5 0 Hoxd genes (d13-10) transcripts in the posterior region with increasing influence on genes positioned more centromeric of the cluster (Fig.…”