FOXO3, a gene linked to intelligence and involved in insulin signalling that might trigger apoptosis


Genes linked to intelligence

Researchers discovered that the genes that were the strongest linked to intelligence are ones involved in pathways that play a part in the regulation of the nervous system’s development and apoptosis (a normal form of cell death that is needed in development). The most significant SNP was found within FOXO3, a gene involved in insulin signalling that might trigger apoptosis. The strongest associated gene was CSE1L, a gene involved in apoptosis and cell proliferation.

Does this all mean that intelligence in humans depends on the molecular mechanisms that support the development and preservation of the nervous system throughout an person’s lifespan? It’s possible.

And is it possible to explain intelligence through genetics? This paper suggests it is. Nevertheless, it might be warranted to consider that intelligence is a very complex trait and even if genetics did play a role, environmental factors such as education, healthy living, access to higher education, exposure to stimulating circumstances or environments might play an equally or even stronger role in nurturing and shaping intelligence.

It is also worth considering that the meaning of “intelligence” rather falls within a grey area. There might be different types of intelligence or even intelligence might be interpreted differently: in which category would for example a genius physicist – unable to remember their way home (Albert Einstein) – fall? Selective intelligence? Mozart nearly failed his admission tests to Philharmonic Academy in Bologna because his genius was too wide and innovative to be assessed by rigid tests. Is that another form of selective intelligence? And if so, what’s the genetic basis of this kind of intelligence?

Studies like this are extremely interesting and they do show we are starting to scratch the surface of what the biological basis of intelligence really is.

This article was originally published on The Conversation. Read the original article.

About FOX0

What are they? FOXO proteins are a subgroup of the Forkhead family of transcription factors. This family is characterized by a conserved DNA-binding domain (the ‘Forkhead box’, or FOX) and comprises more than 100 members in humans, classified from FOXA to FOXR on the basis of sequence similarity. These proteins participate in very diverse functions: for example, FOXE3 is necessary for proper eye development, while FOXP2 plays a role in language acquisition. Members of class ‘O’ share the characteristic of being regulated by the insulin/PI3K/Akt signaling pathway. How did this family get named ‘Forkhead’? Forkhead, the founding member of the entire family (now classified as FOXA), was originally identified in Drosophila as a gene whose mutation resulted in ectopic head structures that looked like a fork.

Forkhead proteins are also sometimes referred to as ‘winged helix’ proteins because X-ray crystallography revealed that the DNA-binding domain features a 3D structure with three α-helices flanked by two characteristic loops that resemble butterfly wings.

How many FOXOs are there? In invertebrates, there is only one FOXO gene, termed daf-16 in the worm and dFOXO in the fly. In mammals, there are four FOXO genes, FOXO1, 3, 4, and 6. Hey, what about FOXO2 and FOXO5? FOXO2 is identical to FOXO3 (a.k.a. FOXO3a, as opposed to FOXO3b, a pseudogene). FOXO5 is the fish ortholog of FOXO3. FOX hunting…

FOXO genes were first identified in humans because three family members (1, 3, and 4) were found at chromosomal translocations in rhabdomyosarcomas and acute myeloid leukemias. Just after FOXO factors were identified in human tumor cells, the crucial role of DAF-16 in organismal longevity was discovered in worms.

DAF-16 activity was shown to be negatively regulated by the insulin/PI3K/Akt signaling pathway. Subsequent experiments in mammalian cells showed that mammalian FOXO proteins were directly phosphorylated and inhibited by Akt in response to insulin/ growth factor stimulation. Thus, FOXO factors are evolutionarily conserved mediators of insulin and growth factor signaling.

Why are they important? FOXO transcription factors are at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell-cycle progression, and oxidativestress resistance (Figure 1). For example, FOXO factors can initiate apoptosis by activating transcription of FasL, the ligand for the Fas-dependent celldeath pathway, and by activating the pro-apoptotic Bcl-2 family member Bim. Alternatively, FOXO factors can promote cellcycle arrest; for example, FOXO factors upregulate the cell-cycle inhibitor p27kip1 to induce G1 arrest or GADD45 to induce G2 arrest.

FOXO factors are also involved in stress resistance via upregulation of catalase and MnSOD, two enzymes involved in the detoxification of reactive oxygen species. Additionally, FOXO factors facilitate the repair of damaged DNA by upregulating genes, such as GADD45 and DDB1. Other FOXO target genes have been shown to play a role in glucose metabolism, cellular differentiation, muscle atrophy, and even energy homeostasis.

Is there a connection between FOXO and cancer?

Because FOXO proteins were originally identified in human tumors, and because they play an important role in cell-cycle arrest, DNA repair, and apoptosis — cell functions that go awry in cancer — the FOXO family is thought to coordinate the balance between longevity and tumor suppression. Consistent with this idea, in certain breast cancers, FOXO3 is sequestered in the cytoplasm and inactivated. Expression of active forms of FOXO in tumor cells prevents tumor growth in vivo. Additionally, protein partners of FOXO, such as p53 and SMAD transcription factors, are tumor suppressors. Investigating the ensemble of FOXO protein partners will provide insight into the connection between aging and cancer.


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