Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Raphael Kopan

Abstract

Notch is a transmembrane receptor that mediates short-range signaling between neighboring cells. Notch signaling has been implicated in various cellular and developmental processes essential in the life of metazoans. Specifically, Notch signaling plays a critical role in mammalian skin. Removal of Notch alleles in skin keratinocytes has been associated with an array of phenotypes with varying severity based on the identity and number of remaining Notch receptors. Phenotypes include carcinogenesis: in the case of Notch1 loss), transformation of hair follicles to epidermal cysts and neonatal lethality, the latter seen in the absence of all Notch signaling. Although these phenotypes were previously described, the exact mechanisms underlying them have not been fully understood. This dissertation focuses on obtaining mechanistic insights into some of the observed phenotypes attained by analyses of the local and systemic changes downstream of Notch signaling loss in the skin. In order to examine the direct consequences of Notch loss in keratinocytes, we first focused on intrinsic changes detected at postnatal day 9 in Notch-deficient epidermis in vivo. Our findings helped establish that an additive function of Notch paralogs is required for proper epidermal differentiation and lipid biosynthesis in the epidermis, which in turn lead to formation of a competent skin-barrier. We showed that these functions were executed through both canonical: RBP-j-dependent) and non-canonical Notch signals. Accordingly, we discovered that the defective skin-barrier formed by Notch1-deficient keratinocytes created a sub-acute wound-like microenvironment that explained the tumor promotion seen in the absence of Notch1 in the skin. Therefore, skin carcinogenesis is a non-cell autonomous consequence of Notch deletion in keratinocytes, which represents the end result of a crosstalk between barrier-defective epidermis and its underlying stroma. Besides the intricate interaction between epidermis and its neighboring structures in the skin, we uncovered that defects in epidermal barrier sets off a systemic alarm by secreting thymic stromal lymphopoietin: TSLP), an epithelial-derived cytokine implicated in pathogenesis of asthma and atopic dermatitis. TSLP was highly expressed by Notch-deficient epidermis. Importantly, we were able to show that TSLP was both required and sufficient to cause a lethal systemic B-lymphoproliferative disorder in newborn or asthma in adult mice lacking Notch signaling in the skin. Overall, this body of work outlines the direct cellular effects of Notch loss, and describes the mechanisms connecting epidermal Notch deletion to its non-cell autonomous local and systemic consequences.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7TB14X8

Download

Share

COinS