Deletion of the homeodomain gene Six3 from kisspeptin neurons causes subfertility in female mice

Shanna N Lavalle; Teresa Chou; Jacqueline Hernandez; Nay Chi P Naing; Michelle Y He; Karen J Tonsfeldt; Pamela L Mellon

doi:10.1016/j.mce.2022.111577

Deletion of the homeodomain gene Six3 from kisspeptin neurons causes subfertility in female mice

Mol Cell Endocrinol. 2022 Apr 15:546:111577. doi: 10.1016/j.mce.2022.111577. Epub 2022 Feb 2.

Authors

Shanna N Lavalle¹, Teresa Chou², Jacqueline Hernandez³, Nay Chi P Naing⁴, Michelle Y He⁵, Karen J Tonsfeldt⁶, Pamela L Mellon⁷

Affiliations

¹ Department of Obstetrics, Gynecology, And Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address: snewton@health.ucsd.edu.
² Department of Obstetrics, Gynecology, And Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address: teresa.chou@northwestern.edu.
³ Department of Obstetrics, Gynecology, And Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address: jah151@ucsd.edu.
⁴ Department of Obstetrics, Gynecology, And Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address: nnaing@ucsd.edu.
⁵ Department of Obstetrics, Gynecology, And Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address: m3he@ucsd.edu.
⁶ Department of Obstetrics, Gynecology, And Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address: ktonsfeldt@health.ucsd.edu.
⁷ Department of Obstetrics, Gynecology, And Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address: pmellon@health.ucsd.edu.

Abstract

The homeodomain transcription factor SIX3 is a known regulator of eye, nose, and forebrain development, and has recently been implicated in female reproduction. Germline heterozygosity of SIX3 is sufficient to cause subfertility, but the cell populations that mediate this role are unknown. The neuropeptide kisspeptin is a critical component of the reproductive axis and plays roles in sexual maturation, ovulation, and the maintenance of gonadotropin secretion. We used Cre-Lox technology to remove Six3 specifically from kisspeptin neurons in mice to test the hypothesis that SIX3 in kisspeptin neurons is required for reproduction. We found that loss of Six3 in kisspeptin neurons causes subfertility and estrous cycle irregularities in females, but no effect in males. Overall, we find that SIX3 expression in kisspeptin neurons is an important contributor to female fertility.

Keywords: Cre/LoxP; Fertility; Hypothalamus; Kisspeptin; Six3.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Eye Proteins* / genetics
Eye Proteins* / metabolism
Female
Gonadotropin-Releasing Hormone / metabolism
Homeobox Protein SIX3
Homeodomain Proteins* / genetics
Homeodomain Proteins* / metabolism
Infertility*
Kisspeptins* / genetics
Kisspeptins* / metabolism
Male
Mice
Nerve Tissue Proteins* / genetics
Nerve Tissue Proteins* / metabolism
Neurons* / metabolism
Neuropeptides / metabolism
Reproduction / physiology

Substances

Eye Proteins
Homeodomain Proteins
Kisspeptins
Nerve Tissue Proteins
Neuropeptides
Gonadotropin-Releasing Hormone

Abstract

Publication types

MeSH terms

Substances

Grants and funding