Biology subjects

Rosenkrantz, J. L.

Publications and source records attributed to Rosenkrantz, J. L..

3 recordsLinked to original sources

bioRxiv2018

Chromosome Removal Via Cellular Fragmentation and Aneuploid Blastomere Exclusion in Primate Embryos

Aneuploidy that arises during meiosis and/or mitosis is a major contributor to early embryo loss. We previously demonstrated that human preimplantation embryos encapsulate mis-segregated chromosomes into micronuclei while undergoing cellular fragmentation and that fragments can contain chromosomal material, but the source of this DNA was unknown. Here, we leveraged the use of a non-human primate model and single-cell DNA-sequencing (scDNA-seq) to examine the chromosomal content of 471 individual samples comprising 254 blastomeres, 42 polar bodies, and 175 cellular fragments from a large number (N=50) of disassembled rhesus cleavage-stage embryos. Our analysis revealed that the frequency of aneuploidy and micronucleation is conserved between humans and macaques and that cellular fragments encapsulate whole and/or partial chromosomes lost from blastomeres. Single-cell/fragment genotyping demonstrated that these chromosome-containing cellular fragments (CCFs) can be either maternal or paternal in origin and display DNA damage via double-stranded breaks. Chromosome breakage and abnormal cytokinesis resulted in reciprocal losses/gains at the terminal ends of chromosome arms, uniparental genome segregation, and mixoploidy between blastomeres. Combining time-lapse imaging with scDNA-seq, we also determined that multipolar divisions at the zygote or 2-cell stage generated chaotic aneuploidy encompassing a complex mixture of maternal and paternal chromosomes. Despite frequent chromosomal mis-segregation at the cleavage-stage, we show that CCFs and non-dividing aneuploid blastomeres exhibiting extensive DNA damage are prevented from incorporation at the blastocyst stage. These findings suggest that embryos respond to chromosomal errors by encapsulation into micronuclei, elimination by cellular fragmentation, and selection against highly aneuploid blastomeres to overcome chromosome instability during preimplantation development.

developmental biology↗

bioRxiv2017

Structurally conserved primate lncRNAs are transiently expressed during human cortical differentiation and influence cell type specific genes

The cerebral cortex has expanded in size and complexity in primates, yet the underlying molecular mechanisms are obscure. We generated cortical organoids from human, chimpanzee, orangutan, and rhesus pluripotent stem cells and sequenced their transcriptomes at weekly time points for comparative analysis. We used transcript structure and expression conservation to discover thousands of expressed long non-coding RNAs (lncRNAs). Of 2,975 human, multi-exonic lncRNAs, 2,143 were structurally conserved to chimpanzee, 1,731 to orangutan, and 1,290 to rhesus. 386 human lncRNAs were transiently expressed (TrEx) and a similar expression pattern was often observed in great apes (46%) and rhesus (31%). Many TrEx lncRNAs were associated with neuroepithelium, radial glia, or Cajal-Retzius cells by single cell RNA-sequencing. 3/8 tested by ectopic expression showed [≥]2-fold effects on neural genes. This rich resource of primate expression data in early cortical development provides a framework for identifying new, potentially functional lncRNAs.

neuroscience↗

bioRxiv2017

Human-specific NOTCH-like genes in a region linked to neurodevelopmental disorders affect cortical neurogenesis

Genetic changes causing dramatic brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and a determinant of neuronal number in the mammalian cortex. We find three paralogs of human-specific NOTCH2NL are highly expressed in radial glia cells. Functional analysis reveals different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation. NOTCH2NL genes provide the breakpoints in typical cases of 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism, and deletions with microcephaly and schizophrenia. Thus, the emergence of hominin-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger hominin neocortex accompanied by loss of genomic stability at the 1q21. 1 locus and a resulting recurrent neurodevelopmental disorder.

neuroscience↗