Genetic Approaches To Understanding Organ Development And Function

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

During this reporting period the Laboratory of Genetics and Physiology has made progress in the understanding of mechanisms used by cytokiens through the JAK/STAT pathway and its negative regulators from the SOCS family. Progress has been made in seveveral organ systems. In extension to our work on mammary tissue we investigated the role of the JAK/STAT pathway in skin and wound healing.[unreadable] [unreadable] Skin and keratinocytes[unreadable] It was well established that the proliferation and differentiation of keratinocytes during wound healing is regulated by cytokines and chemokines, which are secreted by resident and inflammatory cells and activate the transcription factor signal transducer and activator of transcription (STAT)3. However, it was not clear to what extent STAT3 in keratinocytes is activated by gp130-containing receptors. LGP researchers have addressed this question genetically by deleting the suppressor of cytokine signaling (SOCS)3, a negative regulator of gp130-mediated STAT3 activation, from mouse keratinocytes. Floxed SOCS3 alleles were deleted in mice with either an MMTV-Cre or K5-Cre transgene. While both transgenes are active in keratinocytes, the MMTV-Cre deletes floxed genes also in immune cells. Deletion of Socs3 using the MMTV-Cre transgene resulted in aberrant STAT3 activation, impaired wound healing, prolonged secretion of chemokines, a hyperproliferative epidermis, and neutrophil infiltration into wounds. Simultaneous deletion of the Socs3 and gp130 genes restored normal wound healing. Moreover, deletion of Socs3 only in keratinocytes caused impaired wound healing. [unreadable] [unreadable] This study demonstrated that wound healing is controlled in keratinocytes by the gp130-SOCS3-STAT3 pathway and an imbalance of this pathway results in delayed wound healing.[unreadable] [unreadable] Neurons[unreadable] In a collaborative study we demonstrated that growth hormone and erythropoietin control neuronal growth through the use of the transcription factor STAT5. This study opened investigations to use modulators of the JAK/STAT pathway to treat certain neuronal consitions such as stroke.