Homeobox protein SIX3 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''SIX3''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
The SIX homeobox 3 (SIX3) gene is crucial in
embryonic development
In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...
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 controls body temperature, reproductive functions, eating, sleeping, and the display of emotions.
Ve ...
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 (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
that binds to specific
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
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. 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, the master regulator of
eye development. 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 the o ...
), the region in which the
lens
A lens is a transmissive optical device that 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, mitosi ...
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 Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...
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 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 striking, ...
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 with
TLE1
Transducin-like enhancer protein 1 is a protein that in humans is encoded by the ''TLE1'' gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DN ...
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