The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex.

BACKGROUND: Chromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co-repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Here, we show for the first time that MBD3/NuRD function is essential for normal neurogenesis in mice. RESULTS: Deletion of MBD3, a structural component of the NuRD complex, in the developing mouse central nervous system resulted in reduced cortical thickness, defects in the proper specification of cortical projection neuron subtypes and neonatal lethality. These phenotypes are due to alterations in PAX6+ apical progenitor cell outputs, as well as aberrant terminal neuronal differentiation programmes of cortical plate neurons. Normal numbers of PAX6+ apical neural progenitor cells were generated in the MBD3/NuRD-mutant cortex; however, the PAX6+ apical progenitor cells generate EOMES+ basal progenitor cells in reduced numbers. Cortical progenitor cells lacking MBD3/NuRD activity generate neurons that express both deep- and upper-layer markers. Using laser capture microdissection, gene expression profiling and chromatin immunoprecipitation, we provide evidence that MBD3/NuRD functions to control gene expression patterns during neural development. CONCLUSIONS: Our data suggest that although MBD3/NuRD is not required for neural stem cell lineage commitment, it is required to repress inappropriate transcription in both progenitor cells and neurons to facilitate appropriate cell lineage choice and differentiation programmes.We wish to thank Nicola Reynolds for the help with figures; Aoife O’Shaughnessy for the critical reading of the manuscript; Peter Humphreys, the SCI Biofacility staff and Margaret McLeish for technical assistance; Stephanie Hall and Gerard Evan for access to the Laser Capture Microscope and Nathalie Saurat and members of the BH lab for useful discussions. This work was supported by a Wellcome Trust Senior Fellowship in the Basic Biomedical Sciences awarded to BH and a bourse de formation from the Fonds de la Recherche en Santé Québec awarded to EK.This is the final published version of the article. It was originally published in Neural Development (Knock E, et al., Neural Development, 2015, 10:13, doi:10.1186/s13064-015-0040-z). The final version is available at http://dx.doi.org/10.1186/s13064-015-0040-

The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex

Abstract Background Chromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co-repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Here, we show for the first time that MBD3/NuRD function is essential for normal neurogenesis in mice. Results Deletion of MBD3, a structural component of the NuRD complex, in the developing mouse central nervous system resulted in reduced cortical thickness, defects in the proper specification of cortical projection neuron subtypes and neonatal lethality. These phenotypes are due to alterations in PAX6+ apical progenitor cell outputs, as well as aberrant terminal neuronal differentiation programmes of cortical plate neurons. Normal numbers of PAX6+ apical neural progenitor cells were generated in the MBD3/NuRD-mutant cortex; however, the PAX6+ apical progenitor cells generate EOMES+ basal progenitor cells in reduced numbers. Cortical progenitor cells lacking MBD3/NuRD activity generate neurons that express both deep- and upper-layer markers. Using laser capture microdissection, gene expression profiling and chromatin immunoprecipitation, we provide evidence that MBD3/NuRD functions to control gene expression patterns during neural development. Conclusions Our data suggest that although MBD3/NuRD is not required for neural stem cell lineage commitment, it is required to repress inappropriate transcription in both progenitor cells and neurons to facilitate appropriate cell lineage choice and differentiation programmes

Towards Sustainable Aquafeeds: Complete Substitution of Fish Oil with Marine Microalga Schizochytrium sp Improves Growth and Fatty Acid Deposition in Juvenile Nile Tilapia (Oreochromis niloticus)

We conducted a 84-day nutritional feeding experiment with dried whole cells of DHA-rich marine microalga Schizochytrium sp. (Sc) to determine the optimum level of fish-oil substitution (partial or complete) for maximum growth of Nile tilapia. When we fully replaced fish oil with Schizochytrium (Sc100 diet), we found significantly higher weight gain and protein efficiency ratio (PER), and lower (improved) feed conversion ratio (FCR) and feed intake compared to a control diet containing fish oil (Sc0); and no significant change in SGR and survival rate among all diets. The Sc100 diet had the highest contents of 22:6n3 DHA, led to the highest DHA content in fillets, and consequently led to the highest DHA: EPA ratios in tilapia fillets. Schizochytrium sp. is a high quality candidate for complete substitution of fish oil in juvenile Nile tilapia feeds, providing an innovative means to formulate and optimize the composition of tilapia juvenile feed while simultaneously raising feed efficiency of tilapia aquaculture and to further develop environmentally and socially sustainable aquafeeds. Results show that replacing fish oil with DHA-rich marine Sc improves the deposition of n3 LC PUFA levels in tilapia fillet. These results support further studies to lower Schizochytrium production costs and to combine different marine microalgae to replace fish oil and fishmeal into aquafeeds

Initial weight, final weight, weight gain, percentage weight gain, feed conversion ratio (FCR), specific growth rate (SGR), protein efficiency ratio (PER), feed intake, and survival rate of tilapia fed experimental diets.

<p>Initial weight, final weight, weight gain, percentage weight gain, feed conversion ratio (FCR), specific growth rate (SGR), protein efficiency ratio (PER), feed intake, and survival rate of tilapia fed experimental diets.</p

Formulation (g/100g diet) and proximate composition (%) and essential amino acids (% in the weight of diet as is) of five experimental diets for juvenile tilapia.

<p>Formulation (g/100g diet) and proximate composition (%) and essential amino acids (% in the weight of diet as is) of five experimental diets for juvenile tilapia.</p

Fatty acid (% of total fatty acids) content of fillets from Nile tilapia fed experimental diets for 84 days and 42 days sampling events; average ± SE for 15 fish per diet (5 fish/replicate with 3 replicates/diet)^§.

<p>Fatty acid (% of total fatty acids) content of fillets from Nile tilapia fed experimental diets for 84 days and 42 days sampling events; average ± SE for 15 fish per diet (5 fish/replicate with 3 replicates/diet)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0156684#t006fn002" target="_blank">^§</a>.</p

Fatty acid content (% of total fatty acids) of experimental diets.

<p>Fatty acid content (% of total fatty acids) of experimental diets.</p

Linear correlation between the Sc inclusion levels in diet and DHA (mg/100g fillet) deposition in fish fillet.

<p>Each point represents the average value (±SE) of three tanks per diet. The amount of DHA is described by the function of y = 7.1423x + 155.8. The correlation coefficient (r) was 0.9459 (<i>p</i><0.01).</p

Fatty acid content (% of total fatty acids) of lipid sources (menhaden fish oil and whole cell dried <i>Schizochytrium</i> sp) used in the experimental diets.

<p>Fatty acid content (% of total fatty acids) of lipid sources (menhaden fish oil and whole cell dried <i>Schizochytrium</i> sp) used in the experimental diets.</p