Talk:ANAT2341 Lab 1 - Sex Determination

From Embryology


Sex determination (male/female) at the biological level is determined by the presence or absence of the Y chromosome.

Initially, we did not know what this factor was and it was designated the "testis determining factor" (TDF). We now know (since 1990) that TDF is the protein product encoded by the SRY gene on the Y chromosome. Without this gene/protein the potential sex is female (see Male below).

For some time, female was considered the "default" sex in the absence of SRY, we now know this is not the case, with several genes specifically required for ovary formation. In females, sex determination involves at least one X chromosome gene, DAX1 encoding a nuclear hormone receptor.

Another critical genetic issue is related to the presence of two X chromosomes, "gene dosage", and in the case of mammals this is regulated by inactivating one of those X chromosomes in each and every cell (see Female below).

Human idiogram.jpg

Human idiogram

Male (XY)

Human idiogram-chromosome Y.jpg

Sry was discovered (1990) by studying a human XY female, resulting from a deletion in the Y chromosome that did not allow testis development. Subsequent mapping of this deletion allowed isolation and characterization of the SRY gene.

There is a suggestion that SRY may allow testes development by acting to inhibit DAX1, which is expressed in the indifferent gonad at the same time. The mechanism of an inhibitor inhibiting and inhibitor is seen in some other developing systems.

  • encodes a 204 amino acid protein (Mr 23884 Da) that is a zinc-finger transcription factor.
  • transcription factors bind to specific sites of DNA and regulates the transcription (expression) of other genes, we still do not know all the genes SRY regulates.
  • expressed when testes begin to form, in gonadal tissue and does not require the presence of germ cells.

Notes: The Y chromosome is much smaller than the X chromosome and by definition, cannot contain important genes for other cellular functions.

Nomenclature, capital letters are used for human genes (SRY) and lower case letters are used for the equivalent genes in other species (sry).

Links: Sex reversal in humans caused by abnormal X-Y exchange | Fig. 2 - image

Female (XX)

Human idiogram-chromosome X.jpg
  • In contrast to the Y chromosome, the X chromosome contains about 5% of the haploid genome and encodes house-keeping and specialized functions.
  • The genetic content of the X chromosome has been strongly conserved between species.
Macaque Xi at interphase 02.jpg

Macaque Xi at interphase

1961 - In order to have correct levels of X chromosome gene/protein expression (gene dosage).
  • females must "inactivate" a single copy of the X chromosome (Xi) in each and every cell.
  • this inactivated chromosome can be identified in female blood cells as the "Barr body".
Model for XIST RNA spread from X inactivation center.jpg

Model for XIST RNA spread from X inactivation center

1991 - The initiator of the X inactivation process was discovered.
  • regulated by a region on the inactivating X chromosome encoding an X inactive specific transcript (XIST).
  • acts as RNA and does not encode a protein.
  • Furthermore X inactivation occurs randomly throughout the embryo.
  • generating a mosaic of maternal and paternally derived X chromosome activity in all tissues and organs.

Links: Signaling in genital development | Fig. 1 - image | X Chromosome Inactivation - Epigenetics 1

Primordial Germ Cells

Stage7 primitive streak labelled.jpg

Human Embryonic Disc (Stage 7)

  • Primordial Germ Cells (PGCs) are thought to be the first population of cells to migrate through the primitive streak in early gastrulation.

Week 3

  • Human embryonic disc showing the primitive streak region where gastrulation occurs, generation the trilaminar embryo.
  • Arrows indicate direction of cell migration through the streak.
Stage9 bf2-primordial germ cell region.jpg

Human Embryo (Stage 9) primordial germ cell region

  • This population of cells then lie at the hindgut and yolk sac junctional region and later migrate into the germinal ridge in early embryonic development.
Mouse gonad sex determination 01.jpg

Mouse gonad Sertoli and Germ Cells

  • It is not the primordial germ cells which respond to SRY presence or absence, but the supporting cells within the developing gonad.

Sry Signaling[1]

  • red - Sertoli cells, showing Fgf9 expression (following Sry expression FGF9 is a downstream signaling molecule).
  • green - Germ cells and endothelial cells, showing PECAM expression.

Practical 12: Sex Determination | Early Embryo | Late Embryo | Fetal | Postnatal | Abnormalities | 2011 Audio


  1. <pubmed>16700629</pubmed>| PLoS Biol.

Additional Information

The information shown below is not part of today's Practical.

Mouse- gonadal supporting cell development.jpg

Mouse - gonadal supporting cell development

Genes implicated in sexual development in mammals

Table below modified from Table 1. Genes implicated in sexual development in mammals in recent review article.<pubmed>17237341</pubmed>| Physiol. Rev.

Gene Protein Function Gonad Phenotype of Null Mice Human Syndrome
Bipotential gonad
Wt1 Transcription factor Blockage in genital ridge development Denys-Drash, WAGR, Frasier syndrome
Sf1 Nuclear receptor Blockage in genital ridge development Embryonic testicular regression syndrome
Lhx9 Transcription factor Blockage in genital ridge development a
Emx2 Transcription factor Blockage in genital ridge development a
M33 Transcription factor Gonadal dysgenesis a
Testis-determining pathway
Gata4/Fog2 Transcription/cofactor Reduced Sry levels, XY sex reversal a
Sry Transcription factor XY sex reversal XY sex reversal (LOF); XX sex reversal (GOF)
Sox9 Transcription factor XY sex reversal Campomelic dysplasia, XX sex reversal (GOF)
Sox8 Transcription factor XY sex reversal in combination with partial loss of Sox9 function a
Fgf9 Signaling molecule XY sex reversal a
Dax1 Nuclear receptor Impaired testis cord formation and spermatogenesis Hypogonadism
Pod1 Transcription factor XY sex reversal a
Dhh Signaling molecule Impaired differentiation of Leydig and PM cells XY gonadal dysgenesis
Pgdra Receptor Reduction in mesonephric cell migration a
Pgds Enzyme No phenotype a
Arx Transcription factor Abnormal testicular differentiation X-linked lissencephaly with abnormal genitalia
Atrx Helicase ND ATRX syndrome
Insl3 Signaling factor Blockage of testicular descent Cryptorchidism
Lgr8 Receptor Blockage of testicular descent Cryptorchidism
Hoxa10 Transcription factor Blockage of testicular descent Cryptorchidism
Hoxal1 Transcription factor Blockage of testicular descent Cryptorchidism
Amh Hormone No Müllerian duct degeneration Persistent Müllerian duct syndrome
Misrl1 Receptor No Müllerian duct degeneration Persistent Müllerian duct syndrome
Pax2 Transcription factor Dysgenesis of mesonephric tubules a
Lim1 Transcription factor Agenesis of Wolffian and Müllerian ducts a
Dmrt1 Transcription factor Loss of Sertoli and germ cells XY femaleb
Ovary-determining pathway
Wnt4 Signaling molecule Müllerian duct agenesis, testosterone synthesis, and coelomic vessel formation XY female (GOF)
FoxL2 Transcription factor Premature ovarian failure BPES
Dax1 Nuclear receptor XY sex reversal (GOF) XY sex reversal (GOF)

  • BPES - blepharophimosis-ptosis-epicanthus inversus syndrome
  • GOF - gain-of-function mutation
  • LOF - loss-of-function mutation
  • ND - not determined
  • WAGR - Wilms' tumor-aniridia-genitourinary malformations-mental retardation

a No mutations in human sexual disorders identified to date.

b Candidate gene for 9p deletion, XY sex reversal.