HOXB13 homeodomain protein is cytoplasmic throughout fetal skin development.

Substantial evidence suggests that HOX homeobox genes regulate aspects of body development, including hair formation. We initially isolated the HOXB13 gene from human fetal skin in experiments designed to identify candidate genes that regulate scarless fetal wound healing. Although the HOX homeodomain proteins have been proposed to function as transcription factors, we have demonstrated previously that substantial fractions of the HOXB6 and HOXB4 proteins are localized to the cytoplasm throughout epidermal development. The purpose of the current study was to identify HOXB13 protein expression patterns in developing skin to elucidate potential mechanisms by which this protein might regulate aspects of tissue development and healing. HOXB13 protein expression was detected throughout the developing epidermis, with weaker signal observed in the early developing dermis. Epidermal HOXB13 signal was detected over the entire body surface, but surprisingly, essentially all of the signal was cytoplasmic in developing skin. Low-level HOXB13 protein expression was detected in adult skin and within the telogen hair follicle, and a portion of the residual signal in adult epidermis was nuclear. Expression in hyperproliferative skin conditions remained cytoplasmic with the exception of epidermis associated with Kaposi's sarcoma, which showed strong HOXB13 expression that was partially localized to the nucleus.

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation.

The HOX homeodomain proteins are fundamental regulators of organ and tissue development, where they are thought to function as transcription factors, and HOX gene expression has been associated with numerous types of cancers. Previous studies have demonstrated that enforced expression of the HOXB4 protein transforms cultured fibroblasts and leads to a selective expansion of the hematopoietic stem cell pool, suggesting that this protein might play a role in cellular proliferation. In support of this concept, we now show that enforced expression of HOXB4 in human neonatal keratinocytes results in increased cellular proliferation and colony formation as well as decreased expression of the alpha-2-integrin and CD44 cell surface adhesion molecules. We previously have reported HOXB4 gene expression in the basal and suprabasal layers of developing human skin and now show extensive HOXB4 mRNA in psoriatic skin and basal cell carcinoma. In fetal human skin HOXB4 protein expression was both nuclear and cytoplasmic within epidermal basal cells and in hair follicle inner and outer root sheath cells, whereas strong nuclear signals were observed in the bulge region. In adult skin, HOXB4 protein expression was both nuclear and cytoplasmic, but was predominantly localized to the intermediate and differentiated cell layers. In contrast to the striking gradient patterns of HOX gene and protein expression previously described in developing spinal cord and limb, HOXB4 protein was uniformly detected in all regions of the fetal and adult skin. Although little HOXB4 signal localized to proliferative cell layers, as marked by proliferating cell nuclear antigen (PCNA) staining, in normal adult epidermis, nuclear HOXB4 protein expression substantially overlapped with PCNA-positive cell in a series of samples of hyperproliferative skin. Taken together, these data suggest that nuclear HOXB4 protein may play a role in the regulation of cellular proliferation/adhesion in developing fetal human epidermis and in hyperproliferation conditions, including cancers, in adult epidermis. Published 2002 Wiley-Liss, Inc.