scholarly journals Mouse models of human disorders of sex development (DSD)

2017 ◽  
Vol 145 ◽  
pp. S148
Author(s):  
Abigail Harris ◽  
Pam Siggers ◽  
Nick Warr ◽  
Gwenn Carre ◽  
Anu Bashamboo ◽  
...  
Keyword(s):  
Mouse Models ◽  
Disorders Of Sex Development ◽  
Sex Development ◽  
Human Disorders

scholarly journals Long-Range Regulation of Key Sex Determination Genes

2021 ◽  
pp. 1-21
Author(s):  
Roberta Migale ◽  
Michelle Neumann ◽  
Robin Lovell-Badge
Keyword(s):  
Sex Determination ◽  
Long Range ◽  
Current Knowledge ◽  
Disorders Of Sex Development ◽  
Sexually Dimorphic ◽  
Protein Coding ◽  
Sex Development ◽  
Human Disorders ◽  
The Many

The development of sexually dimorphic gonads is a unique process that starts with the specification of the bipotential genital ridges and culminates with the development of fully differentiated ovaries and testes in females and males, respectively. Research on sex determination has been mostly focused on the identification of sex determination genes, the majority of which encode for proteins and specifically transcription factors such as SOX9 in the testes and FOXL2 in the ovaries. Our understanding of which factors may be critical for sex determination have benefited from the study of human disorders of sex development (DSD) and animal models, such as the mouse and the goat, as these often replicate the same phenotypes observed in humans when mutations or chromosomic rearrangements arise in protein-coding genes. Despite the advances made so far in explaining the role of key factors such as SRY, SOX9, and FOXL2 and the genes they control, what may regulate these factors upstream is not entirely understood, often resulting in the inability to correctly diagnose DSD patients. The role of non-coding DNA, which represents 98% of the human genome, in sex determination has only recently begun to be fully appreciated. In this review, we summarize the current knowledge on the long-range regulation of 2 important sex determination genes, <i>SOX9</i> and <i>FOXL2</i>, and discuss the challenges that lie ahead and the many avenues of research yet to be explored in the sex determination field.

scholarly journals A tale of two tracts: history, current advances, and future directions of research on sexual differentiation of reproductive tracts†

2019 ◽  
Vol 101 (3) ◽  
pp. 602-616 ◽  
Author(s):  
Fei Zhao ◽  
Humphrey Hung-Chang Yao
Keyword(s):  
Environmental Exposure ◽  
Sexual Differentiation ◽  
Reproductive Tract ◽  
Emerging Technologies ◽  
Disorders Of Sex Development ◽  
Future Directions ◽  
Female Phenotype ◽  
Sex Development ◽  
Human Disorders ◽  
Current Paradigm

AbstractAlfred Jost's work in the 1940s laid the foundation of the current paradigm of sexual differentiation of reproductive tracts, which contends that testicular hormones drive the male patterning of reproductive tract system whereas the female phenotype arises by default. Once established, the sex-specific reproductive tracts undergo morphogenesis, giving rise to anatomically and functionally distinct tubular organs along the rostral–caudal axis. Impairment of sexual differentiation of reproductive tracts by genetic alteration and environmental exposure are the main causes of disorders of sex development, and infertility at adulthood. This review covers past and present work on sexual differentiation and morphogenesis of reproductive tracts, associated human disorders, and emerging technologies that have made impacts or could radically expand our knowledge in this field.

scholarly journals In-vitro cellular reprogramming to model gonad development and its disorders

2021 ◽  
Author(s):  
Nitzan Gonen ◽  
Caroline Eozenou ◽  
Richard Mitter ◽  
Andreia Bernardo ◽  
Almira Chervova ◽  
...  
Keyword(s):  
Sex Determination ◽  
Gonad Development ◽  
Disorders Of Sex Development ◽  
Cellular Reprogramming ◽  
Tubule Formation ◽  
Sex Development ◽  
Human Disorders ◽  
Induced Pluripotent

During embryonic development, mutually antagonistic signaling cascades determine the fate of the bipotential gonad towards a testicular or ovarian identity. Errors in this process result in human Disorders of Sex Development (DSDs), where there is discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in-vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells towards gonadal progenitors. Transcriptomic analysis reveals that the in-vitro-derived murine gonadal cells are equivalent to E11.5 in-vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete AMH, migrate and form tubular structures. The cells derived from a 46,XY DSD female hiPSCs, carrying a NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR/Cas9-mediated correction of the variant rescued the phenotype. This is a robust tool to understand mechanisms of sex-determination and model DSDs.

Molecular mechanisms associated with 46,XX disorders of sex development

2016 ◽  
Vol 130 (6) ◽  
pp. 421-432 ◽  
Author(s):  
Ingrid Knarston ◽  
Katie Ayers ◽  
Andrew Sinclair
Keyword(s):  
Molecular Mechanisms ◽  
Ovarian Development ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Female Gonad ◽  
Ovarian Differentiation ◽  
Sex Development ◽  
Human Disorders ◽  
Genetic Mechanisms

In the female gonad, distinct signalling pathways activate ovarian differentiation while repressing the formation of testes. Human disorders of sex development (DSDs), such as 46,XX DSDs, can arise when this signalling is aberrant. Here we review the current understanding of the genetic mechanisms that control gonadal development, with particular emphasis on those that drive or inhibit ovarian differentiation. We discuss how disruption to these molecular pathways can lead to 46,XX disorders of ovarian development. Finally, we look at recently characterized novel genes and pathways that contribute and speculate how advances in technology will aid in further characterization of normal and disrupted human ovarian development.

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