Another Notch in CD44

lthough the cellular adhesion molecule CD44 is involved in processes ranging from lymphocyte homing to tumor metastasis, it has remained unclear how CD44 transduces the intracellular signals required for such a broad range of activities. On page 755, Okamoto et al. propose a surprising mechanism for CD44 signal transduction: a cytoplasmic domain is cleaved from the protein, after which it translocates to the nucleus and acts directly as a transcriptional regulator. Previous work demonstrated that the extracellular domain of CD44 can be cleaved by membrane-associated proteases, regulating the interaction between CD44 and the extracellular matrix. Okamoto et al. identified a subsequent proteolytic cleavage that releases a fragment of the CD44 intracellular domain (CD44ICD). This fragment translocates to the nucleus, where it activates transcription from the TPA-responsive transcriptional regulation elements found in front of a variety of cellular genes. CD44ICD over-expression also induces CD44 mRNA expression, suggesting a feedback mechanism to regulate CD44 levels. In addition to illuminating the mechanism of CD44 signaling, the new work provides the first example of an adhesion molecule using a type of signal transduction first described for Notch, in which a cleavage fragment of a membrane receptor serves as a transcriptional activator. ᭿ A CD44 can enter and signal in the nucleus. The leg bone's connected to the…cerebellum? n a result that bodes well for medical applications of stem cells, Priller et al. report on page 733 that bone marrow-derived stem cells can differentiate into apparently normal Purkinje neurons in an adult mouse brain. Although previous work demonstrated that bone marrow transferred into an irradiated mouse could give rise to cells I A bone marrow cell (yellow) can develop into a functional Purkinje neuron. expressing neuronal markers, the authors are the first to identify donor-derived neurons that appear to be morphologically normal and functional, and to determine that the donor-derived cells survive as the mouse ages. The authors transferred the green fluorescent protein (GFP) gene into donor bone marrow cells, and then identified GFP-expressing cells in the brains of mice that received the transplanted bone marrow. Donor-derived Purkinje cells were not seen four months after transplantation, but had appeared by 12 months posttransplantation and persisted at least three months beyond that, observations that encompassed most of the lifespan of the mice. Priller et al. speculate that the delayed colonization of the cerebellum by the donor cells may be due to the death of the recipient's …