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Molecular Aspects of Sex Development in Mammals: New Insight
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Molecular Aspects of Sex Development in Mammals: New Insight

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 60483

Special Issue Editors

Dr. Silvano Bertelloni

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Guest Editor
Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy
Interests: disorders/differences of sex development (DSD); children with DSD; testis function; puberty; bone health; hormonal substitutive therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Laura Audì

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Guest Editor
Growth and Development Research Unit, Vall d’Hebron Research Institute (VHIR), Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Interests: Genetics of rare endocrine diseases
Prof. Dr. Christa Flück

E-Mail
Guest Editor
Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Interests: Steroid hormone defects, DSD

Special Issue Information

Dear Colleagues,

The mechanisms producing males and females via sexuate reproduction have fascinated humans since ancient times, but only since the last century and especially through immense efforts in genetics-related knowledge of the molecular mechanisms governing sex development and dimorphism in humans and in other mammals have they been elucidated. It is now clear that early events during embryogenesis controlled by master sex-determining genes (GSD) trigger both male and female sex-specific pathways. New genetic and analytical methods permitted the discovery of these male and female sex pathways and allowed one to understand the molecular basis of disorders (or differences) of sex development (DSD). This Special Issue aims to provide an update of current knowledge in the field of DSD by review articles and original research papers. Manuscripts on the molecular mechanisms of sex development, on their phenotypic expression and pathogenetic background, as well as on new techniques to explore DSD in clinical practice are welcome.

Dr. Silvano Bertelloni
Dr. Laura Audì
Prof. Dr. Christa Flück
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (9 papers)

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Editorial

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3 pages, 202 KiB  
Editorial
Molecular Aspects of Sex Development in Mammals: New Insight for Practice
by Laura Audí, Silvano Bertelloni and Christa E. Flück
Int. J. Mol. Sci. 2020, 21(23), 9146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239146 - 30 Nov 2020
Viewed by 1213
Abstract
Disorders (or differences) of sex development (DSD) are congenital conditions characterized by atypical development of genetic, gonadal or phenotypic sex [...] Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)

Review

Jump to: Editorial

12 pages, 288 KiB  
Review
Brain Sex Differences Related to Gender Identity Development: Genes or Hormones?
by Jiska Ristori, Carlotta Cocchetti, Alessia Romani, Francesca Mazzoli, Linda Vignozzi, Mario Maggi and Alessandra Daphne Fisher
Int. J. Mol. Sci. 2020, 21(6), 2123; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062123 - 19 Mar 2020
Cited by 46 | Viewed by 23242
Abstract
The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the most relevant studies on the biological basis of sexual development, and in particular, it focuses on the impact [...] Read more.
The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the most relevant studies on the biological basis of sexual development, and in particular, it focuses on the impact of sex hormones and genetic background on the development of sexual differentiation and gender identity. The authors conducted a search of published studies on Medline (from January 1948 to December 2019). The evidence suggests that the sexual dimorphic brain could be the anatomical substrate of psychosexual development, on which gonadal hormones may have a shaping role during prenatal and pubertal periods. Additionally, according to several heritability studies, genetic components may have a role, but a promising candidate gene has not been identified. Even though growing evidence underlines the primary role of biological factors on psychosexual development, further studies are necessary to better explain their complex interactions. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
14 pages, 1023 KiB  
Review
Oligogenic Origin of Differences of Sex Development in Humans
by Núria Camats, Christa E Flück and Laura Audí
Int. J. Mol. Sci. 2020, 21(5), 1809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051809 - 06 Mar 2020
Cited by 30 | Viewed by 4130
Abstract
Sex development is a very complex biological event that requires the concerted collaboration of a large network of genes in a spatial and temporal correct fashion. In the past, much has been learned about human sex development from monogenic disorders/differences of sex development [...] Read more.
Sex development is a very complex biological event that requires the concerted collaboration of a large network of genes in a spatial and temporal correct fashion. In the past, much has been learned about human sex development from monogenic disorders/differences of sex development (DSD), but the broad spectrum of phenotypes in numerous DSD individuals remains a conundrum. Currently, the genetic cause of less than 50% of DSD individuals has been solved and oligogenic disease has been proposed. In recent years, multiple genetic hits have been found in individuals with DSD thanks to high throughput sequencing. Our group has been searching for additional genetic hits explaining the phenotypic variability over the past years in two cohorts of patients: 46,XY DSD patients carriers of NR5A1 variants and 46,XY DSD and 46,XX DSD with MAMLD1 variants. In both cohorts, our results suggest that the broad phenotypes may be explained by oligogenic origin, in which multiple hits may contribute to a DSD phenotype, unique to each individual. A search for an underlying network of the identified genes also revealed that a considerable number of these genes showed interactions, suggesting that genetic variations in these genes may affect sex development in concert. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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22 pages, 1416 KiB  
Review
Molecular Characterization of XX Maleness
by Romina P. Grinspon and Rodolfo A. Rey
Int. J. Mol. Sci. 2019, 20(23), 6089; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20236089 - 03 Dec 2019
Cited by 21 | Viewed by 7755
Abstract
Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies [...] Read more.
Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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20 pages, 1070 KiB  
Review
Pluripotent Cell Models for Gonadal Research
by Daniel Rodríguez Gutiérrez and Anna Biason-Lauber
Int. J. Mol. Sci. 2019, 20(21), 5495; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215495 - 04 Nov 2019
Cited by 6 | Viewed by 4069
Abstract
Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous conditions not as rare as previously thought. Part of the obstacles in proper management of these patients [...] Read more.
Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous conditions not as rare as previously thought. Part of the obstacles in proper management of these patients is due to an incomplete understanding of the genetics programs and molecular pathways involved in sex development and DSD. Several challenges delay progress and the lack of a proper model system for the single patient severely hinders advances in understanding these diseases. The revolutionary techniques of cellular reprogramming and guided in vitro differentiation allow us now to exploit the versatility of induced pluripotent stem cells to create alternatives models for DSD, ideally on a patient-specific personalized basis. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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22 pages, 43355 KiB  
Review
Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology
by Leendert H. J. Looijenga, Chia-Sui Kao and Muhammad T. Idrees
Int. J. Mol. Sci. 2019, 20(20), 5017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205017 - 10 Oct 2019
Cited by 27 | Viewed by 4464
Abstract
The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY [...] Read more.
The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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35 pages, 2047 KiB  
Review
46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features
by Federico Baronio, Rita Ortolano, Soara Menabò, Alessandra Cassio, Lilia Baldazzi, Valeria Di Natale, Giacomo Tonti, Benedetta Vestrucci and Antonio Balsamo
Int. J. Mol. Sci. 2019, 20(18), 4605; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184605 - 17 Sep 2019
Cited by 29 | Viewed by 5645
Abstract
The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for [...] Read more.
The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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18 pages, 2195 KiB  
Review
The Insulin/IGF System in Mammalian Sexual Development and Reproduction
by Yasmine Neirijnck, Marilena D. Papaioannou and Serge Nef
Int. J. Mol. Sci. 2019, 20(18), 4440; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184440 - 09 Sep 2019
Cited by 54 | Viewed by 6164
Abstract
Persistent research over the past few decades has clearly established that the insulin-like family of growth factors, which is composed of insulin and insulin-like growth factors 1 (IGF1) and 2 (IGF2), plays essential roles in sexual development and reproduction of both males and [...] Read more.
Persistent research over the past few decades has clearly established that the insulin-like family of growth factors, which is composed of insulin and insulin-like growth factors 1 (IGF1) and 2 (IGF2), plays essential roles in sexual development and reproduction of both males and females. Within the male and female reproductive organs, ligands of the family act in an autocrine/paracrine manner, in order to guide different aspects of gonadogenesis, sex determination, sex-specific development or reproductive performance. Although our knowledge has greatly improved over the last years, there are still several facets that remain to be deciphered. In this review, we first briefly outline the principles of sexual development and insulin/IGF signaling, and then present our current knowledge, both in rodents and humans, about the involvement of insulin/IGFs in sexual development and reproductive functions. We conclude by highlighting some interesting remarks and delineating certain unanswered questions that need to be addressed in future studies. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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9 pages, 231 KiB  
Review
The Role of International Databases in Understanding the Aetiology and Consequences of Differences/Disorders of Sex Development
by Salma Rashid Ali, Angela Lucas-Herald, Jillian Bryce and Syed Faisal Ahmed
Int. J. Mol. Sci. 2019, 20(18), 4405; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184405 - 07 Sep 2019
Cited by 25 | Viewed by 3078
Abstract
The International Disorders of Sex Development (I-DSD) and International Congenital Adrenal Hyperplasia registry (I-CAH) Registries were originally developed over 10 years ago and have since supported several strands of research and led to approximately 20 peer-reviewed publications. In addition to acting as an [...] Read more.
The International Disorders of Sex Development (I-DSD) and International Congenital Adrenal Hyperplasia registry (I-CAH) Registries were originally developed over 10 years ago and have since supported several strands of research and led to approximately 20 peer-reviewed publications. In addition to acting as an indispensable tool for monitoring clinical and patient-centered outcomes for improving clinical practice, the registries can support a wide nature of primary and secondary research and can also act as a platform for pharmacovigilance, given their ability to collect real world patient data within a secure, ethics approved virtual research environment. The challenge for the future is to ensure that the research community continues to use the registries to improve our understanding of Disorders of Sex Development (DSD). Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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