SRY mRNA in one-cell human embryos.

[Teresa Binstock]

Subject: SRY mRNA in one cell human embryos implies that sex 
differentiation begins no later than in one cell human embryos, ie, well 
before hormones are expressed by fetal gonads.


BACKGROUMD:
In May of 1994 I presented a poster entitled Sex Differentiation: Modifying
the Paradigm, wherein I called attention to the fact the gonadal/hormonal
sexual differentiation (SD) are a subset of biological SD. In other words
some biological SD is genomic yet is neither gonadal nor hormonal. 
     Early this summer of 1995 I posted to several Net discussion groups a
hastily reassembled version of that poster. While I was enacting this
summer's series of postings, a very important, recent article lay unread
among my piles of articles. 
     What follows is a calling attention to that important new article
about SRY, the gene usually responsible for male-pattern gonadal
development in XY organisms (ie the gene whose lack in XX organisms usually
results in female-pattern gonadal development). 


                       SRY-BASED SEX DIFFERENTIATION
                  MAY BEGIN IN THE ONE-CELL HUMAN EMBRYO


The presence of SRY mRNA from as early as the one-cell stage in human 
embryos suggests that at least some aspects of sexual differentiation may 
be occurring well prior to gonadal/hormonal differentiation (Ref 1)

Several additional references document that (i) SRY-related products 
modify chromatin structure (Ref 2), and thus (ii) may alter gene expression
(Ref 3,4) in sexually dimorphic ways well prior to the first documented
appearances of the gonadal ridge in humans, thus well prior to the first
appearance of gonadal hormones. 

Following the references is a brief section of comments.

REFERENCE re: EARLY EXPRESSION OF SRY

Ref 1:
Expression of SRY transcripts in preimplantation human embryos. 
     Fiddler, M., Abdel-Rahman, B., Rappolee, D.A. and Pergament, E. 
     American.Journal.of.Medical.Genetics 55:80-84, 1995. 

"We have examined the expression of SRY mRNA in individual in vitro
fertilized preimplantation human embryos; because of ethical constraints,
these studies were confined to embryos with one and three pronuclei. Using
a sensitive reverse transcriptase- polymerase chain reaction (RT-PCR)
assay, we observed SRY mRNA at the one-cell through the blastula stages but
not in spermatozoa. These results indicate that the de novo transcription
of this sex- specific gene occurs at a developmental time considerably
earlier than that of gonadal differentiation. Our results also indicate
that in vitro fertilized embryos with one pronucleus are likely to be
diploid."


REFERENCE re: SRY & CHROMATIN

Ref 2:
  Ferrari S.  Harley VR.  Pontiggia A.  Goodfellow PN.  Lovell-Badge R. 
  Bianchi ME.
  SRY, like HMG1, recognizes sharp angles in DNA.
  EMBO Journal.  11(12):4497-506, 1992 Dec.
Abstract
  "HMG boxes are DNA binding domains present in chromatin proteins, general
  transcription factors for nucleolar and mitochondrial RNA polymerases,   
  and gene- and tissue-specific transcriptional regulators. 
     The HMG boxes of HMG1, an abundant component of chromatin, interact
specifically with four-way junctions, DNA structures that are cross-shaped
and contain angles of approximately 60 and 120 degrees between their arms.
     We show here also that the HMG box of SRY, the protein that determines
the expression of male-specific genes in humans, recognizes four-way
junction DNAs irrespective of their sequence. In addition, when SRY binds
to linear duplex DNA containing its specific target AACAAAG, it produces a
sharp bend. Therefore, the interaction between HMG boxes and DNA appears to
be predominantly structure-specific. The production of the recognition of a
kink in DNA can serve several distinct functions, such as the repair of
DNA lesions, the folding of DNA segments with bound transcriptional
factors into productive complexes or the wrapping of DNA in chromatin."


TWO REFERENCE re: CHROMATIN & GENE EXPRESSION:

Ref 3:
    Adams RL.
    Eukaryotic DNA methyltransferases--structure and function. [Review]
    Bioessays.  17(2):139-45, 1995 Feb.
Abstract
  "Methylation of DNA plays an important role in the control of gene
  expression in higher eukaryotes. This is largely achieved by the   
  packaging of methylated DNA into chromatin structures that are
inaccessible to transcription factors and other proteins. Methylation
involves the addition of a methyl group to the 5-position of the cytosine
base in DNA, a reaction catalysed by a DNA (cytosine-5) methyltransferase.
     This reaction occurs in nuclear replication foci where the chromatin   
  structure is loosened for replication, thereby allowing access to
  methyltransferases. Partly as a result of their recognising the presence
  of a methylcytosine on the parental strand following replication, these
  large enzymes are able to maintain the distribution of methyl groups 
  along  the DNA of somatic cells and, thereby, maintain tissue-specific  
  patterns of gene expression."


Ref 4:
    Owen-Hughes T.  Workman JL.
    Experimental analysis of chromatin function in transcription control.
    Critical Reviews in Eukaryotic Gene Expression.  4(4):403-41, 1994.
Abstract
  "Chromatin structure plays a crucial role in the regulation of eukaryotic
  gene transcription. Nucleosomes and higher orders of chromatin structure
  repress promiscuous gene expression by increasing its dependence on the
  function of activator proteins that regulate transcription in eukaryotic
  cells. Here we review several parameters governing the dynamic
  interactions between transcription factors and chromatin structures.
     These include functions of the core histones and their modification by
  acetylation, histone H1, HMG proteins, nucleosome positioning, DNA
  replication, cooperative nucleosome-binding by transcription factors,
  histone chaperones and nucleosome displacement, the SWI/SNF protein
  complex, and higher-order domains of chromatin structure. All of these
  impact on the interactions of transcription factors with chromatin
  templates. Experimental analysis of these parameters provides new 
  insights into mechanisms of eukaryotic transcription regulation."



TERESA COMMENT:

Research into biological aspects of male/female brain differences (i) is 
omissional if only gonadal/hormonal differentiation is considered, 
and (ii) is inaccurately conceived if "sex differentiation" is presumed 
to be the equivalent of "gonadal/hormonal sex differentiation". In fact,
gonadal/hormonal-SD is only one kind of biological SD; in other words,
g/h-SD is a subset of biological SD -- a fact having ramifications to the
Nature component of Nature/Nurture discussions and related research.


                            ******************


Teresa C. Binstock, Researcher
Developmental & Behavioral Neuroanatomy
Denver
                         Teresa.Binstock at UChsc.edu