SMAD4 LIMB SKELETON

"The Role of SMAD4-mediated BMP Signal Transduction in Determination of Digit Identities, Initiation of Chondrogenesis, and Skeletal Development"

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 Obiettivo del progetto (Objective)

'The limb bud is a system of paradigmatic value to analyze vertebrate organogenesis. One major question is when and how the chondrogenic progenitors of the limb skeleton are determined. Recent studies suggest that digit identities are only fixed during advanced autopod development by BMP signal transduction. Here, I propose an in-depth analysis of the underlying signaling systems using mouse limb buds to gain insight into the requirement of Smad4-dependent and independent BMP signaling for chondrogenesis. Furthermore, the relevance of these findings to engineering cartilage and bone from adult mesenchymal stem cells will also be investigated, which is of significant biomedical relevance towards efforts to improve human health.

Aim 1. BMP signaling in determination of digit identities and chondrogenesis. These processes are disrupted in Smad4 deficient mouse limb buds. Therefore, I will study the cellular and molecular alterations of Smad4-/- in comparison to other mutant and wild-type limb bud mesenchymal cells.

Aim 2. Identification and functional analysis of the molecular networks controlling Sox9 expressing digit progenitors. The transcriptomes of digit and interdigit mesenchymal regions of wild-type and mutant autopods will be analyzed. Such identified candidate regulators will be investigated further to identify the networks governing determination of Sox9 expressing digit progenitor cells.

Aim 3. The potential relevance for adult skeletal repair and engineering of cartilage and bone tissue from mesenchymal stem cells. Comparative molecular and functional analysis to provide insights into the similarities of limb bud and adult mesenchymal stem cells.'

Descrizione progetto (Article)

Scientists have proven that bones, tendons and ligaments are formed due to programmed differentiation of cells called chondrocytes during embryonic development. BMPs are responsible for initiating so-called chondrogenesis through SMAD-dependent and p38 MAPK-dependent pathways.

Until recently, scientists were unable to determine the importance of SMAD4 in chondrogenic differentiation or pinpoint its function. To elucidate its role and understand the early bone formation process, they initiated the SMAD4 LIMB SKELETON project.

The mouse limb model proved particularly useful for these studies. Scientists inactivated Smad4 in some mouse embryos and studied differences in chondrogenesis. Comparison revealed that SMAD4 is critical for onset of chondrogenic differentiation in limb buds and regulation of actin cytoskeletal dynamics.

In Smad4-deficient limb buds, researchers observed disruption in formation of Sox9-positive digit primordia and limb skeletal elements. They also noted a lack of collagen type II expression where collagen type II is a marker for chondrogenic differentiation. Other critical factors such as cadherin complexes, Gremlin1 protein and Semaphorin ligands that are also affected as a result of Smad4 deficiency were also identified.

Researchers successfully isolated and characterised a population of mesenchymal stromal cells (MSCs)/progenitor cells from the adult mouse bone marrow. Ongoing research studies funded via a http://www.snf.ch/en/funding/programmes/sinergia/Pages/default.aspx (Sinergia) network grant are comparing similarities and differences in chondrogenic differentiation between these adult MSCs and limb bud mesenchymal cells. Study outcomes should reveal the differences in bone and cartilage developmental processes.

Project activities have provided novel insight into the factors driving bone and cartilage formation during embryonic development. Such knowledge could prove particularly useful in developing innovative bone and cartilage replacements. The ultimate beneficiaries would be the progressively ageing populations who will eventually need treatments for fractures such as hip or knee replacements.