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| Same Protein for Genital Structures Influences Female and Male Brain Differences |
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| SciMed - Neuroscience | |||||||||
| TS-Si News Service | |||||||||
| Friday, 10 April 2009 14:00 | |||||||||
 Dunedin, New Zealand. Researchers have discovered a new mechanism that contributes to differences between male and female brains and behaviors, while highlighting fundamental anatomical structures that are ordinarily in alignment but can vary under the influences of physical processes.Researchers at the University of Otago in Dunedin (Maori Ôtepoti) found that male mice lacking the MIS
 hormone show subtle changes in their brain anatomy, with behavior more akin to that of female mice. The research team's findings appear in the Proceeding of the National Academy of Science (PNAS).It is well known that sexual dimorphism in the reproductive tract is defined in part by the preeminence of specialized ducts: Müllerian [N1] in females and Wolffian [N2] in males. The embryos of both sexes have Müllerian (or paramesonephric) ducts. They develop into reproductive organs of females, forming the fallopian tubes, uterus, and the upper portion of the vagina. The ducts degenerate in males, where male reproductive organs are formed from the adjoining Wolffian.
Development of the Müllerian ducts is controlled by the presence or absence of sex steroids and an anti-müllerian hormone, referred to here as the Müllerian inhibiting substance (MIS) [N3]. Scientists have been aware of MIS, which only occurs in men, for about 100 years. But it was always thought to have a single function in male development — to prevent the formation of a female's uterus.
However, the Otago research indicates that MIS has a wider influence. Dr. Ian Mclennan, the senior author, says "MIS had not previously been considered of as a hormone involved in brain function ... the research team had been completely surprised by the new finding." [N4]
EmbryogenesisMale embryogenesis. MIS is responsible for the regression of Müllerian ducts, or uterine precursors, in the male fetus. The testes produce the anti-müllerian hormone, which inhibits development of the Müllerian ducts, except for the vestigial vagina masculina and the appendix testis.
The vagina masculina is the prostatic utricle (L. "pouch of the prostate"). It is a small indentation located in the prostatic urethra and is the male homologue of the female fallopian tubes, uterus, and vagina. The structure is often described as a blind duct leading nowhere, but it does serve a function since it is flanked laterally by openings of the ejaculatory ducts. By contracting during intercourse, it opens the ejaculatory ducts to allow passage of semen. [N5]
Disturbances in this otherwise standard develomental process can lead to Persistent Müllerian Duct Syndrome (PMDS). Typically a congenital disorder in humans, PMDS features can include undescended testes (cryptorchidism), the presence of a small, underdeveloped uterus, and/or other Müllerian duct derivatives.
Female embryogenesis. The absence of an anti-müllerian hormone results in the standard development of female reproductive organs, including the oviducts, uterus, upper vagina, and cervix.
Developmental disturbances may result in the complete or partial absence of a uterus, vagina, and cervix (Mullerian agenesis) in 1:5000 women. If malformed, the vagina is shortened and intercourse may in some cases be difficult and painful. Kidney problems, hearing loss, and bone malformations are less commmon but important symptioms.
Females and MalesAssociate Professor McLennan says people tend to think of the obvious differences in sexual anatomy when thinking of "males" and "females".
"However, sex differences occur throughout the entire body. Outside of the primary reproductive organs, the range of male and female characteristics overlap, creating what we call 'sex biases' that actually only exist as a generalisation, at the level of the population, such as men being taller than women. This is not always the case, but is an accepted difference between men and women.
"The sex-biases in the body do not define a person's sex or sexuality. The brain is one of the organs with the greatest sex biases, giving rise to many subtle differences in the behaviour of the sexes. Empathy, for example, has a female bias, but some of the greatest men are empathetic. ... girls engage in less rough and tumble play than boys, but a boy who shuns rough and tumble play is still a boy."
McLennan says discovery of the mechanisms underlying gender-linked characteristics can continue the movement of science toward a greater understanding of human diversity. "The challenge is not just to understand how we develop as women or men, but to also comprehend why the male population encompasses the warrior, the poet, the scientist and wonderful blends of these extremes."
MIS NeurobiologyMany behavioral traits, while not the exclusive to females or males, are more strongly associated with one sex. The work by neurobiologists Ian McLennan, Kyoko Koishi, and their colleagues demonstrate that the cause of these sex-linked behavioral traits goes beyond testosterone, bringing to light a new role for the MIS.
Testosterone imparts the dimorphic nature of the neurons that control sexual function differently in males and females, but testosterone is not present during the most extensive period of fetal brain development.
Both in appearance and sexual behavior the mice is the study are typically male, but their non-reproductive behaviors are more feminine. For example, male mice are known to explore a new environment more extensively than female mice. Yet, male mice with no MIS showed significantly less inclination to explore.
The research team investigated the potential role of MIS as a contributing factor in sex-linked behavioral traits. While the MIS level in males remains high until puberty, its further function is unknown. However, the researchers found that most neurons in mice have an MIS receptor.
They then charted the behaviors of male and female mice missing the gene for MIS or its receptor. Male mice missing either of these, while still undoubtedly male, showed a feminization of some behavioral traits, pointing to a role for MIS that extends well beyond standard gestation.
ImplicationsThe mouse model has proven to be highly valuable in studies of reproduction and embryology, and has done so for many years. "While our research is still very new and has only involved mice to date, it indicates that MIS plays a much broader role in shaping the non-reproductive behaviours of males — such as, the male tendency to explore and spatial processing. But further work is needed to determine which human traits are regulated by MIS."
 The findings also have implications for research into brain disorders, many of which are more common or more severe in one or other of the sexes. "Females are more prone to developing anorexia and Alzheimer's disease, whereas Attention Deficit Hyperactivity Disorder (ADHD), anti-social personality and motor neurone disease have a male bias."
McLennan says the presence of sex-biases in brain disorders suggests that the subtle differences between the brains of males and females alter the course and/or presentation of brain diseases. "This provides a route to explore the mechanisms that underlie brain disorders and options for the development of new therapies, some of which may be male- or female-specific."
A three year study of the affects of MIS on human subjects is currently underway to find out whether the same influences can be identified in human behaviors.
"The role of MIS does not however diminish the importance of societal influences. While MIS may determine some male characteristics, the totality of a given man is a result of complex interplay between MIS, other biological factors and the social world in which he lives," says McLennan.
Finally, the Otago team's demonstration of MIS influence on embryogenesis raises important questions about human development processes upstream from the viable fetus. Considerable scientific effort is underway that contributes to a better understanding of brain and spinal cord formation, a process that precedes implementation of the overall anatomical body plan. Unexpected variation at any stage, without sufficient correction, can lead to a possible mismatch of the brain and body. The research reported here is a crucial contribution toward fully resolving these types of questions.
Notes[N1] The Müllerian ducts are named after Johannes Peter Müller (14 July 1801 — 28 April 1858), a German physiologist, comparative anatomist, and ichthyologist. Müller described development of the ducts that carry his name in Bildungsgeschichte der Genitalien (1830).
[N2] The Wolffian ducts are named after Caspar Friedrich Wolff (18 January 1733 — 22 February 1794), a German physiologist and one of the founders of embryology. Wolff described the mesonephros and its ducts in his 1759 dissertation Theoria Generationis. His grounbreaking paper reconciled previous work by Aristotle and William Harvey while proposing an entirely new model for plant and animal development in which organs are formed in differentiated layers from undifferentiated cells.This was a direct challenge to prevailing "seed" (preformation) theories and belief in the human homunculus that sits in sperm, waiting to emerge. [N3] The Müllerian inhibiting substance (MIS) is also known as the Müllerian inhibiting factor (MIF) or Müllerian inhibiting hormone (MIH). It is a protein encoded by the AMH gene. [N4] Dr. Ian Mclennan speaking on Radio New Zealand (8 March 2009), as reported by Joanne Proctor of HBS-NZ. [N5] A Practical treatise on sexual disorders of the male and female. Robert William Taylor (1897; 3rd ed. 1905). FundingThe research was supported through a Marsden Fund (Te Pûtea Tangahau A Marsden) grant and an Otago Research Grant.
ContributorsPostdoctoral fellow Dr Andrew Clarkson (Neurological Foundation), doctoral students Pei-Yu Wang and Floriane Imhoff, undergraduate student Anna Protheroe and technician Nicola Batchelor were key contributors to the research.
Author contributions: P.-Y.W., A.P., A.N.C., F.I., K.K., and I.S.M. designed research; P.-Y.W., A.P., A.N.C., F.I., and K.K. performed research; I.S.M. analyzed data; and I.S.M. wrote the paper. CitationMüllerian inhibiting substance contributes to sex-linked biases in the brain and behavior. Pei-Yu Wang, Anna Protheroe, Andrew N. Clarkson, Floriane Imhoff, Kyoko Koishi, and Ian S. McLennan. PNAS published online before print: 0902253106v1 (April 9, 2009). doi: 10.1073/pnas.0902253106
Download PDF Abstract Many behavioral traits and most brain disorders are common to males and females but are more evident in one sex than the other. The control of these subtle sex-linked biases is largely unstudied and has been presumed to mirror that of the highly dimorphic reproductive nuclei. Sexual dimorphism in the reproductive tract is a product of Müllerian inhibiting substance (MIS), as well as the sex steroids. Males with a genetic deficiency in MIS signaling are sexually males, leading to the presumption that MIS is not a neural regulator. We challenge this presumption by reporting that most immature neurons in mice express the MIS-specific receptor (MISRII) and that male Mis -/- and Misrii -/- mice exhibit subtle feminization of their spinal motor neurons and of their exploratory behavior. Consequently, MIS may be a broad regulator of the subtle sex-linked biases in the nervous system.Keywords: anti-Müllerian hormone, exploratory behavior, motor neuron, sexual dimorphism. The TS-Si News Service is a collaborative effort by TS-Si.org editors, contributors, and corresponding institutions. The sources can include the cited individuals and organizations, as well as TS-Si.org staff contributions. Articles and news reports do not necessarily convey official positions of TS-Si, its partners, or affiliates.We welcome your comments. Use the form below to leave a public comment or send private correspondence via the TS-Si Contact Page. We will not divulge any personal details or place you on a mailing list without your permission. TS-Si is dedicated to the acceptance, medical treatment, and legal protection of individuals correcting the misalignment of their brains and their anatomical sex, while supporting their transition into society as hormonally reconstituted and surgically corrected citizens. 
 
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