Distinct Consequences of Loss of ERα on Gene Expression and Function of KNDy Neurons at Puberty Onset and in Adulthood

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 112-141-Hypothalamus-Pituitary Development & Biology
Basic/Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-133
Anne Lanjuin*1, C. Geoffrey Lau1, Venkatesh Murthy1 and Catherine Dulac2
1Harvard University, Cambridge, MA, 2Harvard Univ/HHMI, Cambridge, MA
Initiation of sexual development and its repression in juvenile stages are controlled centrally in the hypothalamus by poorly understood mechanisms.  Yet, the extensive medical and social repercussions arising from inappropriate timing of puberty make it critical to understand these mechanisms in detail.  Here we use genetic, genomic, and electrophysiological methods to probe the mechanisms underlying Estrogen-mediated repression of puberty onset by Kisspeptin neurons in mice.  We show that Estrogen receptor alpha (ERα) is required in Kisspeptin/KNDy neurons of the Arcuate (ARC) nucleus of the hypothalamus to repress puberty onset in juvenile females by a mechanism that may not be as straightforward as current models predict.  Qualitative and quantitative measure of KNDy neuron gene expression (Kiss1, Tac2) and electrophysiological measure of KNDy neuron excitability reveals distinct consequences arising from loss of ERa in Kisspeptin neurons at puberty compared to in the mature adult.  Remarkably, despite a dramatic advance in the time of puberty onset in KissCre ERaflox females, at the time of vaginal opening KNDy neurons maintain a profile more characteristic of the normal pubertal-like state than the consequence of loss of ERa in adults.

We performed an RNA-Seq experiment to better understand the gene expression changes occurring in the ARC over sexual development, and in females undergoing early-puberty due to loss of ERa signaling in Kisspeptin neurons.  Overall, gene expression in the ARC from pre-puberty to adult is quite dynamic, with 115 genes changing more than 2 fold (87 up, 28 down (p < 0.05 False Discovery Rate corrected)).  Among these are known KNDy neuron-expressed genes, as well as novel genes not previously identified as part of the KNDy neuron profile, including known and potentially new regulators of HPG axis function.  In contrast, we find only subtle changes in gene expression arising at the time of puberty onset in puberty-advanced females.  Our results have important implications for the understanding of mechanisms underlying the initiation of puberty, and for the general understanding of KNDy neuron function

Nothing to Disclose: AL, CGL, VM, CD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Howard Hughes Medical Institute; National Institute of Health  R01DC009019