Aristaless-related homeobox (Arx) was recently demonstrated to be involved in pancreatic α cell fate specification while simultaneously repressing the β and δ cell lineages. To establish whether Arx is not only necessary, but also sufficient to instruct the α cell fate in endocrine progenitors, we used a gain-of-function approach to generate mice conditionally misexpressing this factor. Mice with forced Arx expression in the embryonic pancreas or in developing islet cells developed a dramatic hyperglycemia and eventually died. Further analysis demonstrated a drastic loss of β and δ cells. Concurrently, a remarkable increase in the number of cells displaying α cell or, strikingly, pancreatic polypeptide (PP) cell features was observed. Notably, the ectopic expression of Arx induced in embryonic or adult β cells led to a loss of the β cell phenotype and a concomitant increase in a number of cells with α or PP cell characteristics. Combining quantitative real-time PCR and lineage-tracing experiments, we demonstrate that, in adult mice, the misexpression of Arx, rather than its overexpression, promotes a conversion of β cells into glucagon- or PP-producing cells in vivo. These results provide important insights into the complex mechanisms underlying proper pancreatic endocrine cell allocation and cell identity acquisition.

Background: The forebrain consists of multiple structures necessary to achieve elaborate functions. Proper patterning is, therefore, a prerequisite for the generation of optimal functional areas. Only a few factors have been shown to control the genetic networks that establish early forebrain patterning. Results and conclusion: Using conditional inactivation, we show that the transcription factor Sp8 has an essential role in the molecular and functional patterning of the developing telencephalon along the anteroposterior axis by modulating the expression gradients of Emx2 and Pax6. Moreover, Sp8 is essential for the maintenance of ventral cell identity in the septum and medial ganglionic eminence (MGE). This is probably mediated through a positive regulatory interaction with Fgf8 in the medial wall, and Nkx2.1 in the rostral MGE anlage, and independent of SHH and WNT signaling. Furthermore, Sp8 is required during corticogenesis to sustain a normal progenitor pool, and to control preplate splitting, as well as the specification of cellular diversity within distinct cortical layers.

buttonhead (btd) encodes an SP1-like transcription factor required for the generation and specification of Drosophila head segments. We identified a murine btd homolog, termed mouse Btd (mBtd), which can support btd-dependent head development in transgenic fly embryos. Functional studies show that mBtd-deficient mice develop to term and die at birth. They exhibit brain malformations, posterior axial skeleton truncations, and shortened limbs. We present evidence that mBtd is required during early limb development to maintain, but not to initiate Wnt/β-catenin-dependent FGF, Shh, and BMP-mediated signaling. The data indicate that mBtd represents a novel key player mediating proximodistal outgrowth of the limb.

Pax3 is a member of the paired-box-containing transcription factors. It is expressed in the developing somites, dorsal spinal cord, mesencephalon and neural crest derivatives. Several loss-of-function mutations are correlated with the Splotch phenotype in mice and Waardenburg syndrome in humans. Malformations include a lack of muscle in the limb, a failure of neural tube closure and dysgenesis of numerous neural crest derivatives. In this study we have used embryonic stem (ES) cells to generate a lacZ knock-in into the Pax3 locus. The Pax3 knock-in Splotch allele (Sp^2G) was used to generate Pax3-deficient ES cells in order to investigate whether, in chimeric embryos, Pax3 is acting cell autonomously in the somites and the neural tube. We found that while Pax3 function is essential for the neuroepithelium and somites, a wild-type environment rescues mutant neural crest cells. In the two affected embryonic tissues, mutant and wild-type cells undergo segregation and do not intermingle. The contribution of mutant cells to the neural tube and the somites displayed temporal differences. All chimeric embryos showed a remarkable contribution of blue cells to the neural tube at all stages analyzed, indicating that the Pax3-deficient cells are not excluded from the neural epithelium while development proceeds. In contrast, this is not true for the paraxial mesoderm. The somite contribution of Pax3^−/− ES cells becomes less frequent in older embryos as compared to controls with Pax3^+/− ES cells. We propose that although Pax3 function is related to cell surface properties, its role may differ in various tissues. In fact, apoptosis was found in Pax3-deficient cells of the lateral dermomyotome but not in the neural tube.