Molecular Roots of the Social Brain

A new $3 million grant from the Simons Foundation to the Institute for Genomic Biology will fund a multidisciplinary collaborative effort by Gene Networks in Neural & Developmental Plasticity (GNDP) theme members to search for similarities in the ways that the brains of many different species, including our own, produce social behavior.  “Our goal,” said GNDP Theme Leader and Principal Investigator Lisa Stubbs, “is to tie the truths we extract from each species together, into a fundamental model of how animal brains respond to social stimulus.”

Just as there is diversity in the physical structure of animals, there is great variation in the structure of their social interactions with other members of their own species.  These interactions can often be grouped into the same broad categories—aggression, mate selection, care of young—but the dynamics vary widely between species.  A female prairie vole mates with one male for life; in contrast, a female mouse shows no such fidelity, while a female stickleback fish allows herself to be chased away by her mate, and a praying mantis female might make a meal of hers.

On a basic level, though, there are shared principles of social behavior across species, just as there are in anatomy.  Animals rely on information from others to guide their behavior during social interactions, and that information, received as primary input, is processed by sets of connected neurons that operate via molecular actions that are deeply conserved, even if the identities of those sets of neurons are not.

IGB researchers will be taking advantage of these commonalities—shared categories of social interactions, and conserved brain biochemistry—to ask whether there are also shared gene actions that guide social behavior.  Alison Bell, Associate Professor of Animal Biology, described the planned study: “we will measure the response to what we think are comparable behaviors in honey bees, stickleback fish, and mice, and look for responses in the same genes, networks, or pathways in each of these organisms.”

Developmental Regulation

The vertebrate T-box transcription factor gene Tbx18 performs a vital role in development of multiple organ systems. Tbx18 insufficiency manifests as recessive phenotypes in the upper urinary system, cardiac venous pole, inner ear, and axial skeleton; homozygous null mutant animals die perinatally.

Neurodevelopment

Auts2 is a newly discovered key neurodevelopmental gene. Mutations in the Auts2 locus cause autism, epilepsy, and mental retardation in humans, but little is known about the function of this gene or its role during neurodevelopment. The Stubbs lab is analyzing the role of AUTS2 in differentiation of neurons in culture to ask what the function of AUTS2 is in normal neurodevelopment. The lab is utilizing a unique translocation mutant called 16Gso which displays epileptic and autistic-like behaviors resulting from a reduction in AUTS2 expression to examine how AUTS2 disruption can lead to abnormal neurodevelopment.

KRAB-ZNF Family

Eukaryotic gene expression is orchestrated by a complex interplay between cis-regulatory elements (CREs) and the proteins that bind to and interact with those DNA sites, including transcription factors (TFs) and various types of chromatin proteins. In metazoan species the cis-elements that regulate gene expression can be found within the gene, directly upstream near the transcription start site, or long distances away from the regulated gene sequence.  These long-distance CREs interact with each other and with gene promoters through chromatin loops, dynamic structures that are unique to specific cell types and cell states.

Many TFs act by recruiting specific chromatin proteins or chromatin remodeling complexes to the CREs, thereby altering their activity and accessibility.  In mammals, one class of chromatin-modifying TFs, called KRAB-ZNFs, dominate the genomic landscape. The KRAB-ZNF family of genes is relatively ancient, but has expanded to a large family, through series of tandem segmental duplications, only in mammals.