Role of BRCA1 in brain development

Abstract

Breast cancer susceptibility gene 1 (BRCA1) is a breast and ovarian cancer tumor suppressor whose loss leads to DNA damage and defective centrosome functions. Despite its tumor suppression functions, BRCA1 is most highly expressed in the embryonic neuroepithelium when the neural progenitors are highly proliferative. To determine its functional significance, we deleted BRCA1 in the developing brain using a neural progenitor-specific driver. The phenotype is characterized by severe agenesis of multiple laminated cerebral structures affecting most notably the neocortex, hippocampus, cerebellum, and olfactory bulbs. Major phenotypes are caused by excess apoptosis, as these could be significantly suppressed by the concomitant deletion of p53. Certain phenotypes attributable to centrosomal and cell polarity functions could not be rescued by p53 deletion. A double KO with the DNA damage sensor kinase ATM was able to rescue BRCA1 loss to a greater extent than p53. Our results suggest distinct apoptotic and centrosomal functions of BRCA1 in neural progenitors, with important implications to understand the sensitivity of the embryonic brain to DNA damage, as well as the developmental regulation of brain size.

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

“…Brca1 knockout mice are embryonically lethal (Liu et al, 2014) whereas transgenic mice with reduced Brca1 expression specifically in neural progenitor cells display increased apoptosis and only survive untill postnatal day 19 (Pao et al, 2014). BRCA1 has also been implicated in the absence of neural tube closure in spina bifida meningomyelocele (Gowen et al, 1996; King et al, 2007).…”

Induced Cre‐mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high‐fat diet

“…For example, individuals with BRCA1 mutations may have reduced mitochondrial respiration or alterations in skeletal muscle metabolic function or both; however, this has not been empirically tested. The growing number of reports regarding changes in skeletal muscle, coupled with evidence in the brain and cardiovascular system (2, 3), suggest a role for Brca1 function in tissues outside of the mammary gland. Considering the vast number of mutations in the BRCA1 gene, it is critical that more studies be pursued to address Brca1 function to identify possible cellular mechanisms regulated by the protein.…”

Potential impact of primate-specific SVA retrotransposons during the evolution of human cognitive function

“…The BRCA1 gene, for instance, which is associated with an SVA F insertion and is one of the hubs in SVA integrated functional network (Figure 2), was shown to be in a cross talk with the estrogen receptor ESR1 . 23,24 BRCA1 is also known to have a strong role in the control of brain size, 25,26 especially in regions responsible for learning, memory, muscle control and balance. Interestingly, structurally related PGR (progesteronedependent transcription factor) binding sites were shown to be enriched in ancient mammalian TEs linked to evolution of pregnancy, 27 and LTR and Alu elements were also shown to be strongly associated with genes relevant to reproduction.…”