Catherine Dulac - Sex Battles in the Brain
About the Lecture
The expression of certain genes depends on whether they were inherited from the mother or the father, a phenomenon known as imprinting. Catherine Dulac has discovered that a surprisingly large number of brain genes are imprinted, often in complex ways. Her findings have broad implications for understanding the inheritance of behavioral traits and disease susceptibility.
Diploid species such as mammals inherit two copies (alleles) of each gene, one from the mother and one from the father. For most genes, the maternal and paternal alleles are expressed at equal levels. But for imprinted genes, only one allele is expressed while the other is silenced.
Twenty years ago, David Haig proposed an evolutionary explanation for imprinting based on genetic conflict between the parents. For species such as mammals, in which the mother contributes more resources (through pregnancy and lactation) than the father, he proposed that genes from the father maximize their fitness by inducing the offspring to consume more maternal resources, whereas genes from mother benefit by sharing resources with their siblings.
This idea was supported by findings that paternally expressed genes tend to promote embryonic growth and maternally expressed genes tend to restrict growth. But sibling competition does not end at birth. It continues after birth, through competition for food, parental attention and so on -- and these behaviors are controlled by the brain.
For this reason, Dulac and colleagues sought to identify imprinted genes within the mouse brain. Using high throughput sequencing technology, they were able to study gene expression patterns in the cortex and hypothalamus of adult mice, and also in the embryonic brain. These mice were derived by crossing two strains of mice that diverge enough to have at least one difference at every gene, allowing the researchers to identify the parental origin of every transcript.
Remarkably, Dulac and colleagues have identified some 1300 imprinted genes – more than ten times the number that were previously known. The expression patterns of these new genes are surprisingly complex. A given gene can be imprinted in the cortex but not in the hypothalamus or vice versa. Or it can be imprinted in the embryo but not in the adult. In some cases, the same gene can give rise to different transcripts with different patterns of imprinting.
There is also an intriguing bias to the pattern of imprinting. In the cortex, the majority of imprinted genes are maternally expressed, whereas in the hypothalamus the majority are paternally expressed. This is consistent with Haig’s model, in which paternally derived genes are expected to promote competitive behaviors whereas maternally derived genes will tend to promote cooperation and sharing with siblings.
Dulac’s team also examined the imprinting of the X-chromosome, which carries a disproportionate number of genes expressed in the brain. Females inherit two copies of the X chromosome, and it is well established that one copy is silenced in every cell, a phenomenon known as X-inactivation. In general, the maternal and paternal X are thought to be silenced with equal probability, but Dulac found that in the cortex, there is a 20% bias toward expression of the maternal X and silencing of the paternal copy.
Finally, Dulac describes how some imprinted genes show different patterns of expression in male and female offspring. For example, an allele inherited from the father can be silenced in male but not female offspring, or vice versa. The significance of this finding is not yet fully clear, but one implication is that it provides a potential explanation for sex-specific disease susceptibility.
Catherine Dulac
Higgins Professor of Molecular and Cellular Biology, Harvard University
Howard Hughes Medical Institute Investigator
Catherine Dulac is investigating the molecular biology of olfactory signaling and is interested in the developmental processes that ensure appropriate connections between the olfactory sensory neurons and the brain.
After completing a Ph.D. in developmental biology at the University of Paris, Dulac joined the laboratory of neuroscientist and HHMI investigator Richard Axel at Columbia University in New York City in 1993. As a postdoc in Axel's lab, Dulac developed a new technology for generating libraries of complementary DNA in individual neurons and, using that technology, identified the first family of pheromone receptors. In 1996, Dulac joined the faculty of Harvard University and was named a Howard Hughes Medical Institute Investigator one year later. She has published more than 50 papers and continues to accumulate honors, including her 2004 election to the American Academy of Arts and Sciences.
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