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Developmental Biology - Sexual Identity

What Makes Maleness?

How do rats without a Y chromosome become male?...

Most mammals inherit chromosomes from both parents - an X from their mother and either an X or Y chromosome from their father. The only way mammals typically develop as male is by inheriting the Y chromosome and its SRY gene — which stimulates male sexual differentiation.
The SRY gene triggers the fetus to produce a protein which binds DNA and stimulates testes to develop and testosterone to be produced. This steroid hormone stimulates all of the male reproductive tract including a surge in testosterone which masculinizes the brain.

Cheryl Rosenfeld DVM, PhD, and professor at the Bond Life Sciences Center of the University of Missouri (MU), examined male and female brains of the endangered species Tokudaia osimensis — the Amami spiny rat — to see how subtle gene changes influence this unusual animal. In this species, all males are absent the Y chromosome. "I'd been interested in these rats for many years now, and it's unclear how sexual differentiation of gonads and brain occurs in this species as both males and females (each) have a single X chromosome."
Unlike most mammals, Amami spiny rat (Tokudaia osimensis) males have no Y chromosome. It was lost during eons of evolution. Females also only have one X chromosome while humans have two.

Working in collaboration with researchers from the University of Miyazaki and the Hokkaido University, Japan, Rosenfeld along with Madison T. Ortega and Nathan J. Bivens of the University of Missouri, isolated RNA from brains of both sexes in order to sequence and compare transcribed strands of data [DNA copied into messenger RNA (mRNA)] stored in brain cell nuclei.
Transcripts are the step between a gene and a protein. They are essentially a piece of RNA encoded to make a particular protein. Subtle variations to that RNA can change the final protein to be more or less potent. Looking at these transcripts, investigators found major differences between male and female brains.

"Several different transcripts or isoforms encode the same gene, and while there might be 10 transcripts from a particular gene, some have more effect on individual cells," Rosenfeld explains. "When we compared males to females, there were several hundred more transcripts upregulated in males than females. Our thought is that as both have the same sex chromosome, these differences could indicate males have more of one potent transcript."

Expression differences in transcripts might also come from epigenetic changes, alterations that turn on or off certain DNA regions, without changing the DNA structure. Potentially, females also have transcripts not expressed due to epigenetic changes. "Our thought is that since both have the same sex chromosome, the resulting differences could be that males might have more of one of the more potent transcripts."
Looking closer, researchers saw many transcripts expressed in males encode zinc finger proteins — genes that can be turned on by SRY and thought to significantly influence sexual development.

It's possible all zinc finger transcripts must be turned on in order to stimulate male sexual differentiation to compensate for the missing SRY.

There are all sorts of mammals with sex chromosomes exceptions. The duckbill platypus has five sets of X and Y, without any differences between males and females. Focusing on sex chromosomes and the SRY gene might even overlook other unknown contributing factors. Rosenfeld explains: By understanding anomalous species, we open up mechanisms regulating gonadal and brain sexual differentiation that are are quite complex."

Results of the research are found in the journal BMC Genomics Part of Springer Nature.

Brain sexual differentiation is sculpted by precise coordination of steroid hormones during development. Programming of several brain regions in males depends upon aromatase conversion of testosterone to estrogen. However, it is not clear the direct contribution that Y chromosome associated genes, especially sex-determining region Y (Sry), might exert on brain sexual differentiation in therian mammals. Two species of spiny rats: Amami spiny rat (Tokudaia osimensis) and Tokunoshima spiny rat (T. tokunoshimensis) lack a Y chromosome/Sry, and these individuals possess an XO chromosome system in both sexes. Both Tokudaia species are highly endangered. To assess the neural transcriptome profile in male and female Amami spiny rats, RNA was isolated from brain samples of adult male and female spiny rats that had died accidentally and used for RNAseq analyses.

RNAseq analyses confirmed that several genes and individual transcripts were differentially expressed between males and females. In males, seminal vesicle secretory protein 5 (Svs5) and cytochrome P450 1B1 (Cyp1b1) genes were significantly elevated compared to females, whereas serine (or cysteine) peptidase inhibitor, clade A, member 3 N (Serpina3n) was upregulated in females. Many individual transcripts elevated in males included those encoding for zinc finger proteins, e.g. zinc finger protein X-linked (Zfx).

This method successfully identified several genes and transcripts that showed expression differences in the brain of adult male and female Amami spiny rat. The functional significance of these findings, especially differential expression of transcripts encoding zinc finger proteins, in this unusual rodent species remains to be determined.

Madison T. Ortega, Nathan J. Bivens, Takamichi Jogahara, Asato Kuroiwa, Scott A. Givan and Cheryl S. Rosenfeld.

Gratitude is extended to all those involved in collecting brain samples from Amami spiny rats and Sarah A. Johnson for assisting in the RNA isolation.

Support was provided by the University of Missouri Informatics Research Core Facility and Bond Life Sciences Center.

Availability of data and materials
The datasets supporting the conclusions of this article are included within the article (and its additional files). The reference transcriptomic library generated for Amami spiny rat as part of these studies is available at: https://www.ncbi.nlm.nih.gov/bioproject/474959.

Authors’ contributions
TJ and AK obtained permissions to collect the samples and shipped them to the University of Missouri. MTO and NJB isolated the RNA and performed the RNAseq analyses. SAG analyzed the data. The manuscripts was written and revised by MTO, NJB, TK, AK, SAG, and CSR. All authors have read and approved the final manuscript.

Ethics approval and consent to participate
T. osimensis is endangered (The IUCN Red List of Threatened Species; https://www.iucnredlist.org/). This species has been protected by the Japanese government as a natural monument since 1972 and Nationally Endangered Species of Wild Fauna and Flora since 2016. With permission from the Agency for Cultural Affairs and the Ministry of the Environment in Japan, tissues were harvested from animals died accidentally during a mongoose eradication project on the island in which this species inhabits. In such cases of accidental death, the Japanese government has approved harvesting of brain and other tissues. A copy of this governmental approval, which has also been translated into English, has been provided to the journal.

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Feb 8, 2018   Fetal Timeline   Maternal Timeline   News  

The potential extinction of Amami spiny rat makes this research more urgent.

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