Dual Role of COUP-TF-Interacting Protein 2 in Epidermal Homeostasis and Permeability Barrier Formation

Abstract

COUP-TF-interacting protein 2 (CTIP2; also known as Bcl11b) is a transcription factor that plays key roles in the development of the central nervous and immune systems. CTIP2 is also highly expressed in the developing epidermis, and at lower levels in the dermis and in adult skin. Analyses of mice harboring a germline deletion of CTIP2 revealed that the protein plays critical roles in skin during development, particularly in keratinocyte proliferation and late differentiation events, as well as in the development of the epidermal permeability barrier. At the core of all of these actions is a relatively large network of genes, described herein, that is regulated directly or indirectly by CTIP2. The analysis of conditionally null mice, in which expression of CTIP2 was ablated specifically in epidermal keratinocytes, suggests that CTIP2 functions in both cell and non-cell autonomous contexts to exert regulatory influence over multiple phases of skin development, including barrier establishment. Considered together, our results suggest that CTIP2 functions as a top-level regulator of skin morphogenesis.

Ctip2/Bcl11b controls ameloblast formation during mammalian odontogenesis

“…Keratinocyte differentiation is defective in Ctip2 Ϫ/Ϫ mice, leading to epidermal hypoplasticity and disruption of the epidermal protective barrier (24). Ctip2 does not appear necessary for keratinocyte formation in skin but, rather, the protein seems likely to play an important role in cellular differentiation, and this may be of particular relevance for other, ectodermally derived tissues, such as the dental epithelium and developing tooth.…”

“…Ϫ/Ϫ mice die perinatally (22,24) but do not exhibit an obvious developmental delay or size difference from WT mice during development (24). Three-dimensional, microCT analyses of 5 Ctip2 Ϫ/Ϫ mice at P0 indicated normal morphology of the craniofacial skeleton and dentitional initiation and organization that were indistinguishable from WT mice (Figs.…”

“…Generation of Ctip2 Ϫ/Ϫ mice on an ICR genetic background has been described (24). All animal experiments were conducted with the approval of the Oregon State University Institutional Animal Care and Use Committee.…”

Coordinated Regulation of Transcription Factor Bcl11b Activity in Thymocytes by the Mitogen-activated Protein Kinase (MAPK) Pathways and Protein Sumoylation

“…Bcl11b interacts indirectly with histone deacetylases (HDACs) within the context of the nucleosome remodeling and deacetylation (NuRD) (33,34) or SIRT1 (35) complexes, both of which are recruited to target promoters by interaction with Bcl11b. Bcl11b also acts as a transcriptional activator in a promoter-dependent manner (22,24,36). However, the mechanistic basis for control of the transcriptional regulatory activity of Bcl11b is largely unknown.…”

“…Disruption of the Bcl11b locus in mice results in defective neuronal (20,21), skin (22), craniofacial (23), and T-cell (20, 24 -26) development. Disruption of the human BCL11B locus has been associated with T-cell malignancies (27)(28)(29), suggesting that the protein acts as a tumor suppressor in T-cells (30).…”