Human Reproductive and Prenatal Genetics

Peter C.K. Leung,Jie Qiao

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128135716
• Topic: Medicina
• Subtopic: Genética en medicina

Human Reproductive and Prenatal Genetics presents the latest material from a detailed molecular, cellular and translational perspective. Considering its timeliness and potential international impact, this all-inclusive and authoritative work is ideal for researchers, students, and clinicians worldwide. Currently, there are no comprehensive books covering the field of human reproductive and prenatal genetics. As such, this book aims to be among the largest and most useful references available.

Named a Highly Commended book in the Basic and Clinical Sciences by the British Medical Association.

• Features chapter contributions from leading international scientists and clinicians
• Provides in-depth coverage of key topics in human reproductive and prenatal genetics, including genetic controls, fertilization and implantation, in vitro culture of the human embryo for the study of post-implantation development, and more
• Identifies how researchers and clinicians can implement the latest genetic, epigenetic, and –omics based approaches

Part I

Reproductive Tract Development and Gametogenesis

Chapter 1

Developmental Genetics of the Male Reproductive System

Marisol O’Neill⁎^,†; Boryana Zhelyazkova⁎^,†; Jeffrey T. White⁎^,‡,§; Nannan Thirumavalavan⁎^,‡; Dolores J. Lamb⁎^{,†,‡,¶ ⁎} Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, United States
^† Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
^‡ Scott Department of Urology, Baylor College of Medicine, Houston, TX, United States
^§ Texas Children's Hospital, Houston, TX, United States
^¶ Department of Urology, Weill Cornell Medical College, New York, NY, United States

Abstract

Male reproductive development is a complex process requiring precise endocrine and genetic signals to regulate morphological changes. In this chapter, we review the genetic cues that induce male sexual differentiation from the bipotential gonad to the development of the testes and penis. To begin, SRY production from the male gonads induces testicular development and Mullerian regression. The newly formed testes must then descend into the scrotum to produce functional sperm. Testicular descent is a biphasic process consisting of INSL3-dependent transabdominal descent and androgen-dependent inguinoscrotal descent. Many genes involved in testicular development are also integral in the development of the external genitalia. The external genitalia develops from a gender neutral genital tubercle that undergoes hormone-driven differentiation. Finally, we examine birth defects that can arise from perturbations in the intricate system that regulates normal male reproductive development.

Keywords

Differentiation; Gonads; Testicular descent; Genital tubercle; Hypospadias; Cryptorchidism

Outline

• Introduction
• Early Testicular Development
• Testicular Descent
  • Transabdominal Phase
  • Inguinoscrotal Phase
  • Genetic Control of Testicular Descent
• Development of the External Genitalia
  • Formation of the Genital Tubercle
  • Formation of the Urethra
  • Differentiation of the Male and Female Genitalia
  • Genetic Control of External Genitalia Ontogeny
• Birth Defects
  • Hypospadias
  • Cryptorchidism
• Conclusion
• References

Abbreviations

aCGH array comparative genomic hybridization

AER apical ectodermal ridge

AHR aryl hydrocarbon receptor

AMH/Amh anti-Mullerian hormone

AR androgen receptor

ARNT2 aryl hydrocarbon receptor nuclear translocator 2

Arx aristaless related homeobox

ATF3 activating transcription factor 3

BMP bone morphogenic protein

cAMP cyclic adenosine monophosphate

Cbx2 chromatin modification and remodeling factor also known as M33

CGRP calcitonin gene related peptide

CNV copy number variant

CREBP cyclic AMP response element binding protein

CRKL CRK like proto oncogene

CYP17A1 cytochrome P450 family 17 subfamily A1

CYP1A2 cytochrome P450 family 1 subfamily A2

Dax1 dosage sensitive sex reversal region on the X chromosome

DGKK diacylglycerol kinase kappa

Dhh desert hedgehog

Dlx distal less

E embryonic day

EphB2 ephrin

ESR1 estrogen receptor 1

FGD1 faciogenital dysplasia protein 1

FGF fibroblast growth factor

FGFR fibroblast growth factor receptor

Gata4 GATA binding protein

GFN genitofemoral nerve

Gli glioma associated oncogene

hCG human chorionic gonadotropin

Hox homeobox

IGF insulin-like growth factor

Igfr1 insulin-like growth factor receptor

INSL3 insulin-like 3

Insr insulin receptor

JNK Jun N terminal kinase

LHR luteinizing hormone receptor

Lhx9 Lim homeobox protein

M33 chromatin modification and remodeling factor also known as Cbx2

MAMLD1 mastermind like domain containing 1

MAPK mitogen activated protein kinase

Mis Mullerian inhibiting substance

NR5A1/Nr5a1 nuclear receptor 5 A1 also known as steroidogenic factor 1

PDE4B phosphodiesterase 4B

Pdgfra platelet derived growth factor receptor

PGCs primordial germ cells

PTPN11 protein tyrosine phosphatase receptor

Ras rat sarcoma

RXFP2 relaxin family of peptide receptor

Sf1 nuclear receptor 5 A1 also known as steroidogenic factor 1

Shh sonic hedgehog

SNP single nucleotide polymorphism

Sox9 SRY box 9

SPAG5 sperm associated antigen 5

SRY/Sry sex determining region

STRBP spermatid perinuclear RNA binding protein

Tbx T box transcription factor

Tfm testicular feminization mutation

VAMP7 vesicle associated membrane protein

WNT wingless

WT1/Wt1 Wilm's tumor 1

Introduction

Early embryonic development occurs in a sex-independent manner. This gender-neutral phase is brief. As the gonads begin to differentiate, male and female structures differentiate. In humans as well as many other mammals, sex is determined by the presence of X and Y chromosomes. The initial driver of male sexual differentiation is the presence of a Y chromosome that contains genes necessary for masculinization. However, the genes that drive sexual differentiation are not restricted to the Y chromosome. Genes across all chromosomes regulate sexual differentiation and are expressed in a sex-specific manner. This type of genetic regulation often occurs in a hormone-dependent manner. In this chapter, we will explore the genetic drivers of sexual differentiation throughout embryonic development.

Early Testicular Development

Sexual reproduction, by definition, is the production of a new living organism by combining the genetic information of two individuals from different sexes. The genetic sex of the embryo (the presence or absence of the Y chromosome) determines the gonadal sex (testis or ovary), which in turn leads to the development of the phenotypic sex (secondary sexual characteristics, such as external genitalia).

The reproductive system ontogeny begins with the formation of the genital ridge on the ventral surface of the mesonephros as paired thickenings of the intermediate mesoderm. The genital ridge is composed of somatic and germ cells. In mice, primordial germ cells (PGCs) are specified in the proximal epiblast and migrate from the primitive streak to the endoderm, which will form the future hindgut. This happens at embryonic day 7.5 (E7.5). Then PGCs migrate along the endoderm to reach the genital ridge at E10.5 to consequently form the embryonic gonad [1–4]. The decision to develop either a testis or an ovary comes from the differentiation of the supporting cells (Sertoli cells in males or granulosa cells in females) according to the genetic sex of the embryo.

The initial stages of genital development are the same for both sexes with sex determination occurring based on the presence of the X or Y chromosomes at E32 for human and E10.5 in mice. The proper development of the gonads is a tightly regulated process and, if disrupted, can lead to the development of disorders of sex development such as gonadal dysfunction, infertility, ambiguous genitalia, etc.

During the early stages of embryonic development, the gonads are bipotential (Fig. 1.1). There are key genes involved in the early growth and survival of the gonads, some of which are Nr5α1, Lhx9, Wt1, Cbx2, and Igf1r. The orphan nuclear receptor Nr5α1 [5] (also known as Ad4BP/Sf1) is a transcription factor that is expressed in the gonads and all primary steroidogenic tissues. Deletion in mice results in complete gonadal and adrenal gland agenesis. One of the genes regulating Nr5α1 is Lhx9 [6] (LIM homeobox protein), which is necessary for gonad formation. The zinc finger transcription factor Wilm's tumor 1 (Wt1) [7], specifically its Wt1-KTS isoform, is also essential for development of the bipotential gonad and ki...