Mouse model systems to study sex chromosome genes and behavior: relevance to humans - PubMed (original) (raw)
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Mouse model systems to study sex chromosome genes and behavior: relevance to humans
Kimberly H Cox et al. Front Neuroendocrinol. 2014 Oct.
Abstract
Sex chromosome genes directly influence sex differences in behavior. The discovery of the Sry gene on the Y chromosome (Gubbay et al., 1990; Koopman et al., 1990) substantiated the sex chromosome mechanistic link to sex differences. Moreover, the pronounced connection between X chromosome gene mutations and mental illness produces a strong sex bias in these diseases. Yet, the dominant explanation for sex differences continues to be the gonadal hormones. Here we review progress made on behavioral differences in mouse models that uncouple sex chromosome complement from gonadal sex. We conclude that many social and cognitive behaviors are modified by sex chromosome complement, and discuss the implications for human research. Future directions need to include identification of the genes involved and interactions with these genes and gonadal hormones.
Keywords: Behavior; Four core genotypes; Klinefelter syndrome; Sex differences; Sexual differentiation; Turner syndrome.
Copyright © 2014 Elsevier Inc. All rights reserved.
Figures
Figure 1. Structural domains of mouse X and Y sex chromosomes
Schematic of the sex chromosomes in mice. PAR (in green), the pseudoautosomal region has sequence homology between X and Y with identical genes that recombine during male meiosis. Sts (in white), the steroid sulfatase gene. NPX (in pink), the non-pseudoautosomal region of X-chromosome genes unique to X. NRY (in yellow), the non-recombining region of Y-chromosome genes unique to Y. Sry (in blue), the sex determining region of Y encoding the testis-determining transcription factor. The centromere is represented as a white circle.
Figure 2. Cross of XXF and XY−Sry to generate Four Core Genotypes (FCG)
Top line: Breeder mice to generate the FCG offspring. The dam is a normal XX female, and the sire is an XY male with a deletion on Y of testis-determining factor rescued by an autosomal transgene. The color of the mouse body denotes gonadal sex: female (F) is pink, and male (M) is blue. The autosomes (A) are in orange with Sry, the sex determining region of Y encoding the testis-determining transcription factor, in blue. PAR (in green), is the pseudoautosomal region. NPX (in pink), is the non-pseudoautosomal region of X- chromosome genes unique to X. NRY (in yellow), is the non-recombining region of Y chromosome genes unique to Y. The X on this region denotes the Sry gene mutation, and all Y-chromosomes have the Sry deletion. The centromere is represented as a white circle. Bottom Line: FCG offspring consisting of the following: XX females, XXF; XY females, XYF; XX males, XXM; and XY males, XYM. Maternally inherited X chromosomes are labeled with a pink X. Paternally inherited X chromosomes are labeled with a blue X. All other depictions are the same as for the breeders on the top line.
Figure 3. Domains of the Y* chromosome
Represented are both the normal Y (on the left) and the Y* chromosomes. The pseudoautosomal region (PAR) of the normal Y has been separated into three domains based on their locations relative to the normal centromere (depicted here as a white circle on the normal Y): proximal (a = red), middle (b = orange), and distal (c = green) domains. The Y* chromosome contains all of the unique Y-genes located in the non-recombining region of Y (NRY, yellow domain) including the sex determining region of Y (Sry, blue bar). A spontaneous translocation event from the X chromosome duplicated the PAR proximal and middle regions of Y* and attached the duplicate domains in an inverted fashion along with a new centromere. Hatched circle, inactive Y-centromere on the Y* chromosome. Note that the Y* chromosome is missing the Sts gene.
Figure 4. Y* meiosis
During metaphase of a 4S gamete, the altered pseudoautosomal region (PAR) of the Y* chromosome pairs with the X PAR in an inverted fashion. To demonstrate the arrangements of the domains of the pseudoautosomal region (PAR) throughout mitosis and recombination of X and Y*, the PAR region has been depicted as three domains based on their locations relative to the normally active centromere (depicted here as a white circle on X): proximal (a = red) domain; middle (b = orange) domain; and distal (c = green) domain. When genetic material is exchanged between X and Y* in the inverted orientation during recombination, the recombined chromatids are different in structure and content of sex chromosome genes compared to the non-recombined chromatids. After recombination and separation of the four unique chromosomes after telophase 1 and 2, four male gametes are produced that differ in content of the following paternal sex chromosomes: X, XY*, Y*X, and Y*. The non-pseudoautosomal region of X (NPX), and the non-recombining region of Y (NRY), are depicted in pink and yellow, respectively. The active Y* centromere is depicted as a white circle, and the inactivate centromere is a circle with stripes. Sry, the sex determining region of Y (blue bar in NRY).
Figure 5. Offspring of the Y* Cross
When an XX female (XXF) is mated with a male possessing a Y* chromosome (XY*M), four different genotypes of offspring are produced from the inheritance of the sire’s sex chromosome. Every pup receives a maternal X chromosome, and in combination with the paternal sex chromosome the four genotypes are: XX female, 2XF; XY*X female, 1XF; XXY* male, 2XM; and XY* male, 1XM. NPX, the non-pseudoautosomal region of X (pink). NRY, the non-recombining region of Y (yellow). PAR, the non-pseudoautosomal region of Y broken into proximal (a = red), middle (b = orange), and distal (c = green) domains.
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