Regulation Of Shh Expression Research Articles

Reversibility of digit loss revisited: Limb diversification in Bachia lizards (gymnophthalmidae).

Strict interpretations of the Dollo's Law lead to postulation that trait loss is irreversible and organisms never recover ancestral phenotypes. Dollo, however, admitted the possibility of reversals in trait loss when predicted differences between reversed (derived) and ancestral forms. Phenotypic signatures from reversals are expected, as the historical context of a reversal in trait loss differs from the initial setting where the trait originally evolved. This article combines morphological and molecular information for Bachia scolecoides to discuss phenotypic and genetic patterns established during processes that reversed digit loss in Gymnophthalmidae (also termed microteiid lizards). Results suggest that pathways leading to the derived tetradactyl state of B. scolecoides comprise particularities in their origin and associated processes. Autopodial bones of B. scolecoides lack digit identity, and muscle anatomy is very similar between manus and pes. Gymnophthalmidae sequence patterns in the limb-specific sonic hedgehog enhancer (ZRS) suggest that regulation of shh expression did not degenerate in Bachia, given the prediction of similar motifs despite mutations specific to Bachia. Persistence of developmental mechanisms might explain intermittent character expression leading to reversals of digit loss, as ZRS signaling pathways remain active during the development of at least one pair of appendices in Bachia, especially if some precursors persisted at early stages. Patterns of ZRS sequences suggest that irreversibility of trait loss might be lineage-specific (restricted to Gymnophthalmini) and contingent to the type of signature established. These results provide insights regarding possible mechanisms that may allow reactivation of developmental programs in specific regions of the embryo.

Gene regulatory landscape of the sonic hedgehog locus in embryonic development.

The organs of vertebrate species display a wide variety of morphology. A remaining challenge in evolutionary developmental biology is to elucidate how vertebrate lineages acquire distinct morphological features. Developmental programs are driven by spatiotemporal regulation of gene expression controlled by hundreds of thousands of cis-regulatory elements. Changes in the regulatory elements caused by the introduction of genetic variants can confer regulatory innovation that may underlie morphological novelties. Recent advances in sequencing technology have revealed a number of potential regulatory variants that can alter gene expression patterns. However, a limited number of studies demonstrate causal dependence between genetic and morphological changes. Regulation of Shh expression is a good model to understand how multiple regulatory elements organize tissue-specific gene expression patterns. This model also provides insights into how evolution of molecular traits, such as gene regulatory networks, lead to phenotypic novelty.

A new function of BMP4: dual role for BMP4 in regulation of Sonic hedgehog expression in the mouse tooth germ

The murine tooth development is governed by sequential and reciprocal epithelial-mesenchymal interactions. Multiple signaling molecules are expressed in the developing tooth germ and interact each other to mediate the inductive tissue interactions. Among them are Sonic hedgehog (SHH), Bone Morphogenetic Protein-2 (BMP2) and Bone Morphogenetic Protein-4 (BMP4). We have investigated the interactions between these signaling molecules during early tooth development. We found that the expression of Shh and Bmp2 is downregulated at E12.5 and E13.5 in the dental epithelium of the Msx1 mutant tooth germ where Bmp4 expression is significantly reduced in the dental mesenchyme. Inhibition of BMP4 activity by noggin resulted in repression of Shh and Bmp2 in wild-type dental epithelium. When implanted into the dental mesenchyme of Msx1 mutants, beads soaked with BMP4 protein were able to restore the expression of both Shh and Bmp2 in the Msx1 mutant epithelium. These results demonstrated that mesenchymal BMP4 represents one component of the signal acting on the epithelium to maintain Shh and Bmp2 expression. In contrast, BMP4-soaked beads repressed Shh and Bmp2 expression in the wild-type dental epithelium. TUNEL assay indicated that this suppression of gene expression by exogenous BMP4 was not the result of an increase in programmed cell death in the tooth germ. Ectopic expression of human Bmp4 to the dental mesenchyme driven by the mouse Msx1 promoter restored Shh expression in the Msx1 mutant dental epithelium but repressed Shh in the wild-type tooth germ in vivo. We further demonstrated that this regulation of Shh expression by BMP4 is conserved in the mouse developing limb bud. In addition, Shh expression was unaffected in the developing limb buds of the transgenic mice in which a constitutively active Bmpr-IB is ectopically expressed in the forelimb posterior mesenchyme and throughout the hindlimb mesenchyme, suggesting that the repression of Shh expression by BMP4 may not be mediated by BMP receptor-IB. These results provide evidence for a new function of BMP4. BMP4 can act upstream to Shh by regulating Shh expression in mouse developing tooth germ and limb bud. Taken together, our data provide insight into a new regulatory mechanism for Shh expression, and suggest that this BMP4-mediated pathway in Shh regulation may have a general implication in vertebrate organogenesis.

Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development

Sonic hedgehog ( Shh) expression in the developing limb is associated with the zone of polarising activity (ZPA), and both are restricted to the posterior part of the limb bud. We show that the expression patterns of Shh and Gli3, a member of the Gli-family believed to function in transcriptional control, appear to be mutually exclusive in limb buds of mouse embryos. In the polydactyly mouse mutant extra toes ( Xt), possessing a null mutation of Gli3, Shh is additionally expressed in the anterior region of the limb bud. The transcript of Ptc, the putative receptor for Shh protein, can be detected anteriorly as well. Other genes known to be involved in limb outgrowth and patterning, like Fibroblast growth factor ( Fgf), Bone morphogenetic protein ( Bmp), and Hoxd are misexpressed in relation to the ectopic Shh expression domain in Xt limb buds. This data suggest that Gli3 is a regulator of Shh expression in mouse limb development.