DLK1 Is a Somato-Dendritic Protein Expressed in Hypothalamic Arginine-Vasopressin and Oxytocin Neurons

Carine Villanueva,Nicolas De Roux,Sandrine Jacquier,Edward E Schmidt

doi:10.1371/journal.pone.0036134

Carine Villanueva, Nicolas De Roux + Show 2 more

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https://doi.org/10.1371/journal.pone.0036134

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Abstract

Delta-Like 1 Homolog, Dlk1, is a paternally imprinted gene encoding a transmembrane protein involved in the differentiation of several cell types. After birth, Dlk1 expression decreases substantially in all tissues except endocrine glands. Dlk1 deletion in mice results in pre-natal and post-natal growth deficiency, mild obesity, facial abnormalities, and abnormal skeletal development, suggesting involvement of Dlk1 in perinatal survival, normal growth and homeostasis of fat deposition. A neuroendocrine function has also been suggested for DLK1 but never characterised. To evaluate the neuroendocrine function of DLK1, we first characterised Dlk1 expression in mouse hypothalamus and then studied post-natal variations of the hypothalamic expression. Western Blot analysis of adult mouse hypothalamus protein extracts showed that Dlk1 was expressed almost exclusively as a soluble protein produced by cleavage of the extracellular domain. Immunohistochemistry showed neuronal DLK1 expression in the suprachiasmatic (SCN), supraoptic (SON), paraventricular (PVN), arcuate (ARC), dorsomedial (DMN) and lateral hypothalamic (LH) nuclei. DLK1 was expressed in the dendrites and perikarya of arginine-vasopressin neurons in PVN, SCN and SON and in oxytocin neurons in PVN and SON. These findings suggest a role for DLK1 in the post-natal development of hypothalamic functions, most notably those regulated by the arginine-vasopressin and oxytocin systems.

Highlights

Delta-Like 1 Homolog (DLK1), known as preadipocyte factor 1 (Pref-1), is a transmembrane protein expressed at the cell surface
To determine Dlk1 isoforms expressed in the hypothalamus and pituitary, reverse transcribed total RNA was PCR amplified using two primers located in exons 4 and 5
The relative expression of the two Dlk1 mRNA isoforms differed between the hypothalamus and pituitary: Dlk1-A was expressed at a higher level than Dlk1-C2 in the hypothalamus, whereas Dlk1-C2 predominated in the pituitary (Figure 1A)

Summary

Introduction

Delta-Like 1 Homolog (DLK1), known as preadipocyte factor 1 (Pref-1), is a transmembrane protein expressed at the cell surface. It comprises an extracellular domain containing epidermal growth factor (EGF)-like repeats, a transmembrane domain, and a short intracellular tail. DLK1 is encoded by a paternally imprinted gene located on chromosome 12 in mouse and chromosome 14 in human. Dlk is widely expressed in embryonic tissues, and its expression level decreases markedly after birth except in a few endocrine glands and a subset of dopaminergic neurons [1,2,3]. Soluble DLK1 is generated by shedding from the transmembrane domain of the extracellular domain cleaved by the ADAM17/TACE enzyme [5,6,7,8]

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