Homeobox protein SIX3 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''SIX3''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Function
The SIX homeobox 3 (SIX3) gene is crucial in
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
by providing necessary instructions for the formation of the
forebrain
In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary ...
and
eye development. SIX3 is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
that binds to specific
DNA sequences, controlling whether the gene is active or inactive. Activity of the SIX3 gene represses
Wnt1 gene activity which ensures development of the forebrain and establishes the proper anterior posterior identity in the
mammalian brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ i ...
. By blocking Wnt1 activity, SIX3 is able to prevent abnormal expansion of the posterior portion of the brain into the anterior brain area.
During retinal development, SIX3 has been proven to hold a key responsibility in the activation of
Pax6
Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the ''PAX6'' gene.
Function
PAX6 is a member of the Pax gene family which is responsible for carrying the gene ...
, the master regulator of
eye development
Eye formation in the human embryo begins at approximately three weeks into embryonic development and continues through the tenth week.Ort, D., David, H."Development of the Eye" Retrieved 22 April 2015. Cells from both the mesodermal and the ecto ...
. Furthermore, SIX3 assumes its activity in the PLE (presumptive lens
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...
), the region in which the
lens
A lens is a transmissive optical device which focuses or disperses a light beam by means of refraction. A simple lens consists of a single piece of transparent material, while a compound lens consists of several simple lenses (''elements ...
is expected to develop. If its presence is removed from this region, the lens fails to thicken and construct itself to its proper morphological state. Also, SIX3 plays a strategic role in the activation of
SOX2.
SIX3 has also been proven to play a role in repression of selected members of the Wnt family. In retinal development, SIX3 is responsible for the repression of
Wnt8b. Also, in forebrain development, SIX3 is responsible for the repression of Wnt1 and activation of SHH,
Sonic Hedgehog gene.
Clinical significance
Mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in SIX3 are the cause of a severe brain malformation, called
holoprosencephaly
Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed ...
type 2 (HPE2). In HPE2, the brain fails to separate into two
hemispheres during early embryonic development, leading to eye and brain malformations, which result in serious facial abnormalities.
A mutant
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
knockout
A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving strikin ...
model has been developed, in which the anterior part of the head was missing due to the atypical increase of
Wnt1 activity. When injected with SIX3, these zebrafish embryos were able to successfully develop a normal forebrain.
When SIX3 was turned off in mice, it resulted in a lack of retina formation due to excessive expression of
Wnt8b in the region where the forebrain normally develops.
Both of these studies demonstrate the importance of SIX3 activity in brain and eye development.
Interactions
SIX3 has been shown to
interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with
TLE1
Transducin-like enhancer protein 1 is a protein that in humans is encoded by the ''TLE1'' gene.
Interactions
TLE1 has been shown to interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex ...
and
Neuron-derived orphan receptor 1.
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
{{Transcription factors, g3
Transcription factors
Developmental neuroscience