DLK1, Notch Signaling and the Timing of Puberty

The factors that trigger human puberty are among the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes, large-scale genome-wide association studies, whole exome sequencing, and whole genome sequencing have been performed in attempts to identify novel genetic factors that modulate the human hypothalamic-pituitary-gonadal axis to result in premature sexual development. Genetic abnormalities involving excitatory and inhibitory pathways regulating gonadotropin-releasing hormone secretion, represented by the kisspeptin (KISS1 and KISS1R) and makorin ring finger 3 (MKRN3) systems, respectively, have been associated with sporadic and familial cases of central precocious puberty (CPP). More recently, paternally inherited genetic defects of DLK1 were identified in four families with nonsyndromic CPP and a metabolic phenotype. DLK1 encodes a transmembrane protein that is important for adipose tissue homeostasis and neurogenesis and is located in the imprinted chromosome 14q32 region associated with Temple syndrome. In this review, we highlight the clinical and genetic features of patients with CPP caused by DLK1 mutations and explore the involvement of Notch signaling and DLK1 in the control of pubertal onset.