DLK1, Notch Signaling and the Timing of Puberty

Abstract

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.

Toxic and Teratogenic Effects of Prenatal Alcohol Exposure on Fetal Development, Adolescence, and Adulthood

“…A critical period in human development that can affect a person's lifelong health status and quality of life is puberty. Many profound maturational changes, including physical, gonadal, and neurodevelopmental changes occur during this time of a person's life [99]. The effects of PAE on an individual can resurface and manifest during the pubertal period.…”

“…In humans, the onset of puberty begins with activation of the hypothalamic-pituitarygonadal (HPG) axis, which leads to gonadotropin-releasing hormone (GnRH) release from the hypothalamus [100]. GnRH release leads to secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland which goes on to activate the gonads and develop the clinical features of puberty and sexual maturity [99]. The HPG axis is first active during the embryonic and early postnatal period of life, and the axis is reactivated during the start of puberty (Figure 2) [99].…”

“…GnRH release leads to secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland which goes on to activate the gonads and develop the clinical features of puberty and sexual maturity [99]. The HPG axis is first active during the embryonic and early postnatal period of life, and the axis is reactivated during the start of puberty (Figure 2) [99]. The exact mechanism by which the HPG axis is reactivated is unknown but has been shown to be partly influenced by genetic factors and environmental factors [100].…”

“…However, the timing of puberty has well-documented health consequences. Early puberty onset, clinically termed precocious puberty, has been associated with diseases such as metabolic syndrome, cardiovascular diseases, and a range of cancers [99,101]. On the other hand, late puberty onset has been associated with diseases including neuropsychiatric diseases, decreased sperm counts, and longer time-to-pregnancy [101,102].…”

“…In various animal studies, PAE had a significant impact on the HPG axis and has been shown to delay the onset of puberty [99,100]. A study with female rat offspring was documented either before puberty onset, around the time of puberty, or in young adulthood after PAE [100].…”