Mice Lacking Paternally Expressed Pref-1/Dlk1 Display Growth Retardation and Accelerated Adiposity

Abstract

Preadipocyte factor 1 (Pref-1/Dlk1) inhibits in vitro adipocyte differentiation and has been recently reported to be a paternally expressed imprinted gene at human chromosome 14q32. Studies on human chromosome 14 deletions and maternal uniparental disomy (mUPD) 14 suggest that misexpression of a yet-to-be-identified imprinted gene or genes present on chromosome 14 causes congenital disorders. We generated Pref-1 knockout mice to assess the role of Pref-1 in growth and in vivo adipogenesis and to determine the contribution of Pref-1 in mUPD. Pref-1-null mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipid metabolites. Furthermore, the phenotypes observed in Pref-1-null mice are present in heterozygotes that harbor a paternally inherited, but not in those with a maternally inherited pref-1-null allele. Our results demonstrate that Pref-1 is indeed paternally expressed and is important for normal development and for homeostasis of adipose tissue mass. We also suggest that Pref-1 is responsible for most of the symptoms observed in mouse mUPD12 and human mUPD14. Pref-1-null mice may be a model for obesity and other pathologies of human mUPD14.

Transit-Amplifying Ductular (Oval) Cells and Their Hepatocytic Progeny Are Characterized by a Novel and Distinctive Expression of Delta-Like Protein/Preadipocyte Factor 1/Fetal Antigen 1

“…Forced expression of dlk in 3T3-L1 cells was reported to inhibit adipogenesis, whereas suppression of dlk promoted the process and accordingly, dlk was suggested to play an important role in the maintenance of the preadipose state. In support of this hypothesis, recent studies on dlk1-null mice demonstrated that lack of dlk expression was associated with obesity 47 while transgenic mice expressing the full ectodomain of dlk (dimeric form) exhibited inhibition of adipogenesis and impairment of adipocyte function leading to development of metabolic abnormalities. 48 Apart from its func- tion in adipocyte differentiation, dlk has been shown to participate in cell-to-cell interactions occurring in the hematopoietic environment of the bone marrow through regulation of stromal cell signals involved in both selfrenewal and differentiation of hematopoietic stem cells into highly proliferative myeloid-erythroid precursors.…”

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

“…One of such factor could be the suppression of GH expression by overexpressed Dlk1. Interestingly, Dlk1 knockout animals are also smaller that the wild-type littermates [43]. This paradox could be explained in part by the ability of Dlk1 to control differentiation.…”

DLK1: increased expression in gliomas and associated with oncogenic activities

“…DLK1 protein, also known as pref-1, SCP-1, Zog, FA1, and pG2 (Lee et al, 1995;Laborda, 2000), is expressed in a variety of murine and human fetal cells, but it is present only in a limited number of adult tissues (Cooper et al, 1990;Jensen et al, 1993;Laborda et al, 1993;Tornehave et al, 1996;Floridon et al, 2000). DLK1 participates in several differentiation processes including adipogenesis (Smas and Sul, 1993;Boney et al, 1996;Garces et al, 1999), hematopoiesis (Moore et al, 1997;Bauer et al, 1998;Kaneta et al, 2000), and adrenal gland development (Cooper et al, 1990;Gaetano et al, 1992), as well as wound healing (Samulewicz et al, 2002); it is also involved in the control of embryonic growth (Schmidt et al, 2000;Takada et al, 2000;Moon et al, 2002). A recent report suggests that DLK1 acts as a negative regulator of Notch1 (Baladron et al, 2005).…”