Available: 10/01/19, Expires: 09/30/20
An elaborate neural network integrating internal and external signals governs the onset of puberty and subsequent fertility. The precise nature and components of this network are not well established, but it is clear that puberty is triggered by the central increase in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which stimulates the secretion of the pituitary gonadotropins, necessary for the activation of gonadal function. Our laboratory uses a translational approach to study the hormones and genes involved in the neuroendocrine regulation of reproductive development, puberty onset and subsequent fertility.
Our approaches include studies of:
- Hypothalamic and pituitary cell models and in vitro studies;
- In vivo mouse models; and
- Patients with clinical reproductive disorders.
Potential Student Roles:
- Assist with reproductive phenotyping of genetically modified mouse models (e.g., pubertal markers, estrous cyclicity);
- Assist with human genetic studies, including review of human patient clinical data to correlate with genetic findings with clinical phenotypes, and DNA sequencing and sequence analysis, including analyses of exome sequence data;
- Contribute to laboratory studies of human inducible pluripotent stem cell (hiPSC)-derived hypothalamic neurons that have been genetically modified by CRISPR-Cas9.
Available: 10/07/19, Expires: 05/31/20
Puberty is the period of transition between childhood and adulthood, characterized by the development of secondary sexual characteristics, gonadal maturation, and attainment of reproductive capacity. In humans, puberty is initiated through activation of the hypothalamic–pituitary–gonadal axis, marked by an increase in pulsatile gonadotropin- releasing hormone (GnRH) release leading to pituitary secretion of luteinizing hormone (LH) and follicle- stimulating hormone (FSH), and subsequent activation of the gonads. Early maturation of the reproductive axis, resulting in pulsatile secretion of GnRH causes central precocious puberty (CPP). Genetic abnormalities in genes involving the excitatory and inhibitory pathways of GnRH secretion, kisspeptin (KISS1 and KISS1R), and makorin-ringer finger 3 (MKRN3), respectively, have been associated with sporadic and familial cases of CPP. More recently, our group identified a complex defect in a gene called delta-like 1 homolog (DLK1) to be associated with CPP in several affected girls. Like MKRN3, DLK1 is a maternally imprinted gene (expressed only by the paternal allele) and single nucleotide polymorphisms in this gene have also been associated with age of menarche when the variant is inherited from the father. Intriguingly, the DLK1 has been shown to be a negative regulator of Notch signaling, which is a cell to cell interaction pathway critical for kisspeptin neuronal development within the mouse hypothalamus. Distinct evidences suggest that Dlk1 is expressed in the mouse mediobasal hypothalamus, which is essential for the neuroendocrine control of GnRH secretion and the timing of puberty onset, in large part through kisspeptin neurons. Taken together, these data suggest that DLK1 may be involved in regulation of kisspeptin neuron formation, maturation, and/or secretion of kisspeptin. However, the exact mechanism by which DLK1 influences the control of pubertal timing remains unknown. The goal of this research project is to elucidate the role and mechanisms of action of DLK1 in the neural network controlling puberty initiation, by using Dlk1 global and conditional (tissue-specific) deficient mouse models.
To this end, we will characterize the pubertal phenotype and identify in vivo possible partners and/or targets of Dlk1 action in the regulation of puberty initiation. The technical aspect of the experiments involves assessment of puberty and reproduction in mice, RNA extraction, cDNA synthesis, quantitative PCR, DNA isolation, mouse genotyping, animal colony maintenance and immunocytochemistry.
We believe that the results of this project may contribute for a better understanding of the physiology of GnRH and the regulation of the reproductive axis, creating new opportunities of diagnosis and treatment.