Biology subjects

Low, T. C. H.

Publications and source records attributed to Low, T. C. H..

3 recordsLinked to original sources

bioRxiv2025

The CPEB ortholog Orb2 regulates brain size through the TRIM-NHL RNA-binding protein, Brain tumor

Neurodevelopment requires precise translational control, the disruption of which is implicated in various neurological disorders, including developmental delays, intellectual disability, and microcephaly. We report a novel role for the Drosophila CPEB-family protein Orb2, a translational regulator, in controlling brain size in a dose dependent manner. Loss of orb2 results in larval brain hypotrophy, whereas orb2 overexpression causes brain overgrowth. We demonstrate that orb2 is required for neural stem cell development from embryonic stages through larval neurogenesis. Structure-function analysis reveals that Orb2 RNA-binding activity promotes brain growth, while its poly-Q and ZZ domains act to restrain overgrowth. Further genetic and biochemical evidence indicates that orb2 functions upstream of the translational repressor Brain tumor (Brat), modulating Brat protein levels and, consequently, influencing brain size. These findings support a model wherein the antagonistic activities of Orb2 and Brat are critical for balanced brain growth during Drosophila neurodevelopment.

developmental biology↗

bioRxiv2025

The ORB2 RNA-binding protein represses translation of its target transcripts during the Drosophila maternal-to-zygotic transition via its functionally conserved Zinc binding 'ZZ' domain

Post-transcriptional regulation is particularly prominent during the maternal-to-zygotic transition (MZT), a developmental phase during which a large proportion of maternally provided mRNAs is repressed and cleared from metazoan embryos. RNA-binding proteins (RBPs) are key components of the post-transcriptional regulatory machinery. We show that the ORB2 RBP, the Drosophila ortholog of human Cytoplasmic Polyadenylation Element Binding Protein (hCPEB) 2-4 protein subfamily, binds to hundreds of maternally provided, rare-codon-enriched mRNAs in early embryos; that ORB2 targets are translationally repressed and unstable during the MZT; identify a U-rich motif enriched in ORB2 targets 3'UTRs; and show that this motif confers ORB2 binding and repression to a luciferase reporter mRNA in S2 tissue culture cells. When tethered to a luciferase reporter, ORB2 and hCPEB2 (but not ORB and hCPEB1) repress translation; the C-terminal Zinc-binding ( ZZ) domain of ORB2 is necessary and sufficient for repression. ORB2 interacts with a suite of post-transcriptional regulators in early embryos; a subset of these interactions is lost upon deletion of the ZZ domain, notably with the Cup repressive complex. ORB2-targets significantly overlap with those previously identified for the repressive RBP, Smaug (SMG). Analysis of the early embryos translatome in the presence or absence of the endogenous ZZ domain shows that mRNAs bound by ORB2 but not by SMG move onto polysomes upon ZZ domain deletion whereas co-bound transcripts do not, consistent with co-regulation of the latter set of transcripts by both RBPs. Our results assign a function to the ZZ domain and position ORB2 in the post-transcriptional network that regulates maternal transcripts during the Drosophila MZT. ARTICLE SUMMARYWe show that Drosophila ORB2, the ortholog of the human CPEB2 RNA-binding protein, negatively regulates its target mRNAs during the maternal-to-zygotic transition via its C-terminal Zinc-binding ( ZZ) domain.

genetics↗

bioRxiv2019

Precise temporal regulation of post-transcriptional repressors is required for an orderly Drosophila maternal-to-zygotic transition

In animal embryos the maternal-to-zygotic transition (MZT) hands developmental control from maternal to zygotic gene products. We show that the maternal proteome represents over half of the protein coding capacity of the Drosophila melanogaster genome and that 2% of this proteome is rapidly degraded during the MZT. Cleared proteins include the post-transcriptional repressors Cup, Trailer hitch (TRAL), Maternal expression at 31B (ME31B), and Smaug (SMG). While the ubiquitin-proteasome system is necessary for clearance of all four repressors, distinct E3 ligase complexes target them: the C-terminal to Lis1 Homology (CTLH) complex targets Cup, TRAL and ME31B for degradation early in the MZT; the Skp/Cullin/F-box-containing (SCF) complex targets SMG at the end of the MZT. Deleting the C-terminal 233 amino acids of SMG makes the protein immune to degradation. We show that artificially persistent SMG downregulates the zygotic re-expression of mRNAs whose maternal contribution is cleared by SMG. Thus, clearance of SMG permits an orderly MZT.

developmental biology↗