Aberrant activation of the human sex-determining gene in early embryonic development results in postnatal growth retardation and lethality in mice

Abstract

Sexual dimorphisms are prevalent in development, physiology and diseases in humans. Currently, the contributions of the genes on the male-specific region of the Y chromosome (MSY) in these processes are uncertain. Using a transgene activation system, the human sex-determining gene hSRY is activated in the single-cell embryos of the mouse. Pups with hSRY activated (hSRYON) are born of similar sizes as those of non-activated controls. However, they retard significantly in postnatal growth and development and all die of multi-organ failure before two weeks of age. Pathological and molecular analyses indicate that hSRYON pups lack innate suckling activities, and develop fatty liver disease, arrested alveologenesis in the lung, impaired neurogenesis in the brain and occasional myocardial fibrosis and minimized thymus development. Transcriptome analysis shows that, in addition to those unique to the respective organs, various cell growth and survival pathways and functions are differentially affected in the transgenic mice. These observations suggest that ectopic activation of a Y-located SRY gene could exert male-specific effects in development and physiology of multiple organs, thereby contributing to sexual dimorphisms in normal biological functions and disease processes in affected individuals.

Brain Sexual Differentiation and Requirement of SRY: Why or Why Not?

“…While SRY may be required for normal male brain function in many therian males, early induction of this gene can also impair neurogenesis as revealed by the hSRY ON mice (Kido et al, 2017 ). The FCG mouse model has been useful in uncoupling the effects of Sry from other Y chromosome-associated genes (Wagner et al, 2004 ; Gatewood et al, 2006 ; Arnold and Chen, 2009 ; Chen et al, 2012 ; Kopsida et al, 2013 ; Kuljis et al, 2013 ; Seney et al, 2013 ; Quinnies et al, 2015 ).…”

“…To understand and uncouple the role of Sry in the brain from other genes on the Y chromosome, various transgenic mouse models have been created. When human SRY (hSRY) is inserted into single-cell mouse embryos (hSRY ON ), this early activation of SRY results in impaired brain neurogenesis and several other disorders, including inability of the resulting pups to suckle, development of fatty liver disease, arrested alveologenesis in the lung, sporadic myocardial fibrosis, and thymic hypoplasia (Kido et al, 2017 ). While the hSRY ON pups are similar in size to wild-type (WT) mice at birth, they undergo retarded postnatal growth and development and die with multi-organ failure before 2 weeks of age.…”

Potential dual functional roles of the Y‐linked RBMY in hepatocarcinogenesis

“…Ectopic expression of MSY genes in other somatic tissues/organs could contribute sex differences in normal development, differentiation and physiology, 67 and disease initiation, progression, and treatment responses in male‐biased manners 15,71 . Indeed, ectopic expression of testis‐specific genes, ie SRY , TSPY , and RBMY , have been observed in normal and diseased somatic cells/tissues, and have been postulated to exert male‐specific actions on the normal and/or diseased development 14‐16,38,74,75 …”

Y chromosome in health and diseases

“…Such impairment results in haploinsufficiency of the RET protein and exacerbation of the pathogenesis of the Hirschsprung's disease, a congenital disorder affecting the ENS differentiation with significantly high male preference [6]. Importantly, aberrant activation of a human SRY transgene during embryogenesis in transgenic mice impairs the normal development of various vital organs, resulting in postnatal growth retardation and lethality [27]. Hence, these studies suggest that aberrant activation of Y chromosome genes, in this case SRY, could disrupt normal development and exacerbate the disease processes, thereby contributing to sex differences in a positive manner(s).…”

“…Accordingly, expression of these testis-specific MSY genes in somatic tissues could exert male-specific effects on the respectively affected organs/cells. We surmise that low-level/spatiotemporal expression of these MSY gene(s) during development/ physiology could produce normal differences between the sexes [5,42,43], and aberrant/high level expression could result in male biases in the pathogeneses of various human diseases [6,27,41]. In particular, TSPY and its X homologue TSPX (TSPYL2) evolved from the same ancestral gene but diverged structurally in their encoded proteins to process contrasting functions in cell cycle regulation and androgen receptor (AR) transactivation [44,45].…”