Genetic and molecular mechanisms of Hox function in mammalian organogenesis; emphasis on musculoskeletal, urogenital and GI/pancreatic development.
One of the most fascinating and important questions in developmental biology and regenerative medicine is the mechanisms by which a stem or precursor cells becomes programmed and differentiates to form all of the various cell types of the fully developed animal. For instance, how does a mesenchymal cell in the anterior part of the body receive the appropriate information to become lung tissue, while another similar cel in the posterior region of the body become kidney? Further, how does early cartilage precursors in the forelimb become an ulna while virtually identical cells in other regions of the body give rise to a rib, a femur or a sacral vertebrae?... While the answer to this question is obviously complex and requires the interaction between growth factors, receptors, extracellular matrix molecules and many transcription factors, many of these factors are used repeatedly in many different places, yet the developmental outcome is distinct. One of the most important group of factors that provides positional information within the developing embryos is the Hox family of transcription factors. Hox genes are expressed in regionally restricted patterns along the anterior-posterior (AP) body axis, as well as the proximal-distal axis of the developing limbs, and this spatial expression is critical for region-specific patterning and differentiation within the developing organism. Continuing genetic and molecular studies demonstrate that Hox function is critical for the formation and development of the neural tube, musculoskeletal system as well as virtually all mesodermal organs. Recent results suggest these factors are also critical for adult tissue maintenance and wound repair, therefore understanding the functional role of these genes in development will inform regenerative thereapies and stem cell repacement strategies. Using mouse as a model system, the Wellik laboratory employs a combination of global loss-of-function (the Wellik lab currently maintains more than 20 Hox mutant lines), conditional loss-of-function, live cell imaging, biochemical and bioinformatic approaches to study the function of Hox genes in development, wound repair and tissue maintenance and regeneration.