Scientists at the Lieber Institute for Brain Development (LIBD) seek to decipher the brain’s innate “development program” that is encoded in the human genome and plays out in multiple stages, and in response to environmental influences, across prenatal life through to adulthood. With its very large and exquisitely curated collection of postmortem human brains, the LIBD team seeks to understand what can alter a healthy brain development trajectory to cause various psychiatric illnesses. They “go to the source” to study genetic mechanisms in actual brain tissues to avoid making questionable inferences from discoveries made with skin or blood samples.
One of the genes involved in brain development that they have carefully studied is called NRG1 (neuregulin 1), known to be associated with schizophrenia. In a paper published September 2014 in the American Journal of Psychiatry, they present the first quantitative analysis of how the NRG1 gene gets expressed during human brain development and across stages of life. The paper identifies a previously unknown mechanism of the NRG1 gene that may be an early developmental risk for schizophrenia.
The paper identifies a previously unknown mechanism of the NRG1 gene that may be an early developmental risk for schizophrenia.
In the paper, Joel E. Kleinman, M.D., Ph.D., Associate Director of Clinical Sciences at LIBD, and colleagues, report measurements of the expression of NRG1 gene variants in cortical brain tissue, beginning at 14 weeks of the prenatal period and extending through age 83. A phenomenon that biologists call alternative splicing generates several different versions of the NRG1 gene. One of these, called NRG1-IV, has been associated in prior research with a gene DNA sequence variant called rs6994992 that has been linked with elevated schizophrenia risk. In this work, the researchers examined the association of rs6994992 with the expression of a specific version of NRG1-IV, dubbed NRG1-IVNV.
Expression levels of NRG1-IVNV were found to be associated with the rs6994992 genotype. The team found, moreover, that NRG1-IVNV, as compared with other versions of NRG1, is uniquely regulated during prenatal and early postnatal development, being first expressed after gestational age 15 weeks, through birth, and until 3 years of age, after which the gene’s expression could not be detected. The proteins generated by the NRG1-IVNV gene were found to be resistant to degradation, and were observed to be enriched in the nucleus of both neurons and human embryonic cells. This suggested to the team that NRG1-IVNV proteins “are biologically distinct NRG1-IV proteins that may be key regulators of early cortical development relevant to the pathophysiology of schizophrenia.”
Dr. Kleinman commented that, “In so far as this transcript [i.e., NRG1-IVNV] is expressed prenatally and disappears after age 3 in human brain, it reminds us still one more time of the importance of both early brain development and postmortem brains in understanding how genetic variation increases risk for schizophrenia."