Insulin-Like Growth Factor 1 Receptor Signaling Regulates Skin Development and Inhibits Skin Keratinocyte Differentiation

Abstract

The insulin-like growth factor 1 receptor (IGF-1R) is a multifunctional receptor that mediates signals for cell proliferation, differentiation, and survival. Genetic experiments showed that IGF-1R inactivation in skin results in a disrupted epidermis. However, because IGF-1R-null mice die at birth, it is difficult to study the effects of IGF-1R on skin. By using a combined approach of conditional gene ablation and a three-dimensional organotypic model, we demonstrate that IGF-1R-deficient skin cocultures show abnormal maturation and differentiation patterns. Furthermore, IGF-1R-null keratinocytes exhibit accelerated differentiation and decreased proliferation. Investigating the signaling pathway downstream of IGF-1R reveals that insulin receptor substrate 2 (IRS-2) overexpression compensates for the lack of IGF-1R, whereas IRS-1 overexpression does not. We also demonstrate that phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1 and 2 are involved in the regulation of skin keratinocyte differentiation and take some part in mediating the inhibitory signal of IGF-1R on differentiation. In addition, we show that mammalian target of rapamycin plays a specific role in mediating IGF-1R impedance of action on keratinocyte differentiation. In conclusion, these results reveal that IGF-1R plays an inhibitory role in the regulation of skin development and differentiation.

Insulin receptor substrate 1 (IRS‐1) plays a unique role in normal epidermal physiology

“…This is in contrast to cells lacking the expression of the IR or the IGF-1R (Sadagurski et al, 2006), where the proliferation process was abnormally decreased. There are several possibilities for interpreting these findings.…”

“…One possible explanation for this finding can be that the IRS-2 protein has no role in the differentiation process and development of skin keratinocytes. Though, previously we have shown that IGF-1R inactivation results in precocious differentiation of skin keratinocytes, and that IRS-2 overexpression prevented this abnormally facilitated differentiation, suggesting that IRS-2 has an inhibitory role in the differentiation process (Sadagurski et al, 2006). However, IRS-2 overexpression had no effects on the normal differentiation process, suggesting that the possible role of IRS-2 in the differentiation process is not direct.…”

“…Further, lack of IR expression results in abnormal differentiation of primary murine skin keratinocytes (Wertheimer et al, 2000. In addition, we have found that lack of IGF-1 receptor (IGF-1R) is associated with facilitated differentiation process, which is mediated partially by the IRS-2 protein (Sadagurski et al, 2006).…”

Overexpression of mIGF-1 in Keratinocytes Improves Wound Healing and Accelerates Hair Follicle Formation and Cycling in Mice

“…4,5 Although generally recognized as a proliferation and survival factor for the skin, IGF-1 was recently also implicated in hair and skin morphogenesis. 6,7 In the skin, its levels must be strictly controlled because overexpression of IGF-1 in proliferating and in differentiating keratinocytes resulted in hyperplasia and tumor formation. 8,9 In addition to its role in skin homeostasis, several studies suggest a role of IGF-1 in skin repair.…”

Mouse Epidermal Keratinocytes in Three-Dimensional Organotypic Coculture with Dermal Fibroblasts Form a Stratified Sheet Resembling Skin

“…23) A three-dimensional culture containing keratinocytes derived from mouse embryonic stem cells grown on a matrix secreted from normal human fibroblasts also forms a thick epithelial sheet that resembles the epidermis of humans but not that of mice. 24) Recently, Sadagurski et al have demonstrated a mouse organotypic coculture using keratinocytes and fibroblasts, 25) which is similar to our coculture, but the keratinocyte sheet remains thicker. 25) The differences between our culture and theirs are the following: collagenase and trypsin for isolation of keratinocytes, FAD and Eagle's medium for cocultures.…”