Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate

Abstract

Preadipocyte factor-1 [Pref-1; also called Dlk1 (Delta-like protein 1)] is made as an epidermal growth factor-repeat containing transmembrane protein that produces a biologically active soluble form by TNF-alpha-converting enzyme (TACE)-mediated cleavage. Soluble Pref-1 activates the MAPK kinase/ERK pathway. In adipose tissue, Pref-1 is specifically expressed in preadipocytes but not in adipocytes and thus is used as a preadipocyte marker. Inhibition of adipogenesis by Pref-1 has been well established in vitro as well as in vivo by ablation and overexpression of Pref-1. SRY (sex determining region Y)-box 9 (Sox9), a transcription factor expressed in preadipocytes to suppress CCAAT enhancer binding protein beta and (C/EBP) delta expression, is required to be down-regulated before adipocyte differentiation can proceed. By activating MAPK kinase/ERK, Pref-1 prevents down-regulation of Sox9, resulting in inhibition of adipogenesis. Furthermore, by inducing Sox9, Pref-1 promotes chondrogenic induction of mesenchymal cells but prevents chondrocyte maturation as well as osteoblast differentiation. Thus, Pref-1 directs multipotent mesenchymal cells toward the chondrogenic lineage but inhibits differentiation into adipocytes as well as osteoblasts and chondrocytes. Pref-1, encoded by an imprinted gene, has also been detected in progenitor cells in various tissues during regeneration and therefore may have a more general role in maintaining cells in an undifferentiated state.

Figure 1

Domain structure of Pref-1 isoforms. EGF (EGF-like repeat), S (signal sequence), JM (juxtamembrane), TM (transmembrane domain), Cyto (cytoplasmic region), and N (N-linked glycosylation sites). Cleavage sites are marked orange.

Figure 2

Pref-1 inhibition of adipogenesis. Membrane-bound Pref-1A and Pref-1B generate 50-kDa soluble Pref-1 by TACE-mediated cleavage at the juxtamembrane region. Binding of the 50-kDa soluble Pref-1 to the putative Pref-1 receptor at the preadipocyte membrane activates MEK/ERK which, in turn, increases Sox9 expression. Sox9 binds to its binding sites at the C/EBPβ and C/EBPδ promoter regions to suppress their transcription, resulting in inhibition of adipocyte differentiation.