SPERM TRANSPORT AND MATURATION

DEVELOPMENT OF THE GONADS ( Primer 21-A )

An important aspect of gonadogenesis is the migration of cell precursors of the male and female gametes from the primary ectoderm into the wall of the yolk sac to become extra-embryonic .

Bone morphogenetic protein , together with signals from the extraembryonic mesoderm and visceral endoderm, specifies pluripotent epiblast cells to become primordial germinal cells (PGCs) . PGCs appear first in the primitive streak and endoderm in the 4-week embryo.

The induction of epiblast cells to PGCs is at the level of transcription regulation mediated by BLIMP1 (B lymphocyte–induced maturation protein 1). In addition, down-regulation of the transcription factor OTX2 increases efficient PGC differentiation. BLIMP1 stimulates the expression of the PGC–specific gene Stella. Stella maintains the pluripotent state of the migrating PGCs by repressing transcription of genes specific to somatic cells. An overexpression of OTX2 and a lack of BLIMP1 prevent the appropriate differentiation and migration of PGCs.

Between 4 and 6 weeks, about 10 to 100 PGCs migrate by ameboid movements from the yolk sac back to the embryo into the wall of the rectum tube. From there, PGCs migrate to the right and left sides of the gonadal ridges through the dorsal mesentery. The initiation of PGC migration is regulated by the cell surface protein IFITM1 (interferon-induced transmembrane protein 1). A lack of IFITM1 protein prevents PGCs from migrating into the endoderm. The expression of Stella persists during the migration of the PGCs to the genital ridge.

How do PGCs find their way to the gonadal ridges?

There is a chemoattractant system that guides PGCs to the gonadal ridges:

• 1.

  SDF1 (stromal-derived factor 1) is expressed at the gonadal ridges and in the surrounding mesenchyme.

• 2.

  The chemokine CXCR4 , expressed by PGCs, is the receptor for SDF1.

A lack of SDF1 or CXCR4 causes very few PGCs to reach the gonadal ridges. If there is an ectopic expression of SDF1, PGCs migrate to the ectopic sites. PGCs, which do not reach the gonadal ridges undergo apoptosis. Bax, a member of the Bcl2 protein family, initiates the apoptotic cascade. Yet, some PGCs avoid apoptosis and can later give rise to extragonadal germ cell tumors .

As PGCs migrate, they proliferate by mitotic division. PGCs reach the gonadal ridges by the 6th week and continue their proliferation as they interact with somatic cells to develop the indifferent gonads .

There are at least three additional factors involved in the migration of PGCs:

• 1.

  The rate of migration and proliferation of PGCs is dependent on the interaction of the c-kit receptor , a tyrosine kinase , with its ligand, stem cell factor (or c-kit ligand) . The c-kit receptor is produced by PGCs; stem cell factor is synthesized by somatic cells along the migration route.

  A lack of c-kit receptor or stem cell factor causes gonads to be deficient in PGCs because they migrate at a significant reduced rate . Recall that hematopoiesis and the development of melanocytes and mast cells depend on the c-kit receptor and its stem cell ligand.

• 2.

  E-cadherin expressed by PGCs is required as PGCs migrate to the hindgut.

• 3.

  PGCs express β 1 integrin , also required for entry to the gonadal ridges.

About 2500 to 5000 PGCs lodge in the mesenchyme and induce cells of the mesonephros and lining coelomic epithelium to proliferate, forming a pair of gonadal ridges . Coelomic epithelial cords grow into the mesenchyme of the gonadal ridge to form the outer cortex and inner medulla of the indifferent gonad.

Development of the testes ( 21-1 ; see Primer 21-A )

Until the seventh week of fetal development, there is one type of gonad common to both genders. This is the „indifferent” stage of gonadal development.

Thereafter, in the female, the cortex develops into the ovary, and the medulla regresses. In the male, the cortex regresses and the medulla forms the testis .

The development of each medulla into a testis is controlled by a transcription factor encoded by the sex-determining region of the Y chromosome (SRY) gene . SRY is also known as testicular-determining factor .

SRY up-regulates Sox9 (for sex determining region Y-box 9) , another transcription factor, whose expression, together with fibroblast growth factor 9, stimulates the development of testicular cords , the precursors of the seminiferous tubules. We have learned in Chapter 4 , Connective Tissue, that Sox9 participates in chondrogenesis, by enabling cells in the perichondrium to differentiate into chondrocytes. Therefore, Sox9 is important for the development of the male reproductive system and the skeleton.

The initial step of testicular development is the differentiation of the Sertoli cell population regulated by the Y chromosome. Fetal Sertoli cells, in turn, modulate the differentiation of the mesenchymal-derived Leydig cells, which initially proliferate under the influence of insulin-like growth factor 1 (IGF-1) . Fetal precursors of peritubular myoid cells and the vasculature develop around the testicular cords.

Fetal Leydig cells produce testosterone stimulated by luteinizing hormone (LH) derived from the fetal adenohypophysis. Testosterone synthesis ceases postnatally, reassumes at puberty and continues throughout adulthood.

Spermatogonia stem cells (SSCs) , derived from PGCs, are mitotically quiescent and located in the center of the testicular cords, surrounded by mitotically dividing Sertoli cells. Close to puberty, SSCs approach the future seminiferous tubular wall and initiate their mitotic amplification cycle , the starting point of spermatogenesis.

A loss of Sox9 function results in XY gonadal dysgenesis in which patients have undeveloped gonadal structures (streak gonads) and absence of virilization (persistence of müllerian-derived structures). Mutations of the Sox9 gene cause campomelic dysplasia involving skeletal abnormalities.

ANDROGEN INSENSITIVITY SYNDROME (AIS)

Androgen insensitivity syndrome (AIS) , or testicular feminization (Tfm) syndrome, results from a defect in the gene controlling the expression of the androgen receptor . This gene is located on the X chromosome. Three phenotypes are observed:

• 1.

  Complete androgen insensitivity syndrome (CAIS ) with female external genitalia.

• 2.

  Partial androgen insensitivity syndrome (PAIS, Reifenstein syndrome) with predominantly female, predominantly male, or ambiguous genitalia.

• 3.

  Mild androgen insensitivity syndrome (MAIS) with male external genitalia. Spermatogenesis and/or pubertal virilization may be impaired.

Although the karyotype is 46, XY, a deficiency in the action of androgen results in the lack of development of the wolffian duct and regression of the müllerian duct because testes development takes place and Sertoli cell–derived AMH is available.

No functional internal genitalia are present in patients with CAIS: the testes remain in the abdomen (recall that androgens stimulate testicular descent). Inguinal hernia with testes can be detected during a physical examination. The testes may be removed after puberty (until feminization is complete) because of the risk of testicular cancer, just like in the undescended testis condition.

The external genitalia develop as female but no uterus is present. Individuals with complete AIS have labia, a clitoris and a short vagina (these structures are not müllerian duct derivatives). Pubic and axillary hair is absent (sexual hair development is androgen-dependent). Individuals with PAIS may have male and female physical characteristics (ambiguous genitalia).

At puberty, the production of both androgen and estradiol increases (the latter from peripheral aromatization of androgens). Androgens cannot inhibit LH secretion (because a defective androgen receptor prevents LH feedback inhibition) and plasma levels of androgens remain high.

AIS can be diagnosed by pelvic ultrasound, hormonal determinations and chromosomal analysis.