The formation of the nervous system requires a balance between proliferation, differentiation, and migration of neural progenitors (NPs). Mutations in genes regulating development impede neurogenesis and lead to neuropsychiatric diseases, including autism spectrum disorders (ASDs) and schizophrenia (SZ). Recently, mutations in nonsense-mediated mRNA decay genes have been associated with ASDs, intellectual disability (ID), and SZ. Here, we examine the function of a gene in the exon junction complex, Rbm8a, in the cortical development. When Rbm8a is selectively knocked out in neural stem cells, the resulting mice exhibit microcephaly, early postnatal lethality, and altered distribution of excitatory neurons in the neocortex. Moreover, Rbm8a haploinsufficiency in the central nervous system decreases cell proliferation in the ganglionic eminences. Parvalbumin+ and neuropeptide Y+ interneurons in the cortex are significantly reduced, and distribution of interneurons are altered. Consistently, neurons in the cortex of conditional knockout (cKO) mice show a significant decrease in GABA frequency. Transcriptomic analysis revealed differentially expressed genes enriched in telencephalon development and mitosis. To further investigate the role of Rbm8a in interneuron differentiation, conditional KO of Rbm8a in NKX2.1 interneuron progenitor cells reduces progenitor proliferation and alters interneuron distributions. Taken together, these data reveal a critical role of Rbm8a in interneuron development, and establish that perturbation of this gene leads to profound cortical deficits.
Schizophrenia (SZ) is a devastating brain disease that affects about 1% of world population. Among the top genetic associations, zinc finger protein 804A (ZNF804A) gene encodes a zinc finger protein, associated with SZ and biolar disorder (BD). Copy number variants (CNVs) of ZNF804A have been observed in patients with autism spectrum disorders (ASDs), anxiety disorder, and BD, suggesting that ZNF804A is a dosage sensitive gene for brain development. However, its molecular functions have not been fully determined. Our previous interactomic study revealed that ZNF804A interacts with multiple proteins to control protein translation and neural development. ZNF804A is localized in the cytoplasm and neurites in the human cortex and is expressed in various types of neurons, including pyramidal, dopaminergic, GABAergic, and Purkinje neurons in mouse brain. To further examine the effect of gene dosage of ZNF804A on neurite morphology, both knockdown and overexpression of ZNF804A in primary neuronal cells significantly attenuate dendritic complex and spine formation. To determine the factors mediating these phenotypes, interestingly, three binding proteins of ZNF804A, galectin 1 (LGALS1), fasciculation and elongation protein zeta 1 (FEZ1) and ribosomal protein SA (RPSA), show different effects on reversing the deficits. LGALS1 and FEZ1 stimulate neurite outgrowth at basal level but RPSA shows no effect. Intriguingly, LGALS1 but not FEZ1, reverses the neurite outgrowth deficits induced by ZNF804A knockdown. However, FEZ1 and RPSA but not LGALS1, can ameliorate ZNF804A overexpression-mediated dendritic abnormalities. Thus, our results uncover a critical post-mitotic role of ZNF804A in neurite and synaptic development relevant to neurodevelopmental pathologies.
33Mammalian brains have largely lost internal neural regeneration capability except for a 34 few discrete neurogenic niches. After brain injury, the cerebral cortex is especially 35 difficult to repair due to its extremely low rate of adult neurogenesis. Previous studies 36 have converted glial cells into neurons, but the total number of neurons generated is 37 rather limited, casting doubt about its therapeutic potential. Here, we demonstrate that 38 high-efficiency neuroregeneration can be achieved in adult mammalian brains by 39 making use of an engineered AAV Cre-FLEX system to convert a large number of 40 reactive astrocytes into functional neurons. Specifically, using a combination of 41 GFAP::Cre and FLEX-NeuroD1 AAV system, we were able to regenerate enough new 42 neurons from astrocytes to cover about 40% of the neurons lost from an ischemic injury 43 (400 NeuN+ new neurons/mm2), compared to previously reported an average of <1% of 44 cortical neurons (2-8 NeuN+ neurons/mm2) in an ischemic-injured adult mammalian 45 cortex. Importantly, this in situ astrocyte-to-neuron conversion process also improved 46 survival of injured pre-existing neurons, (additional 400 neurons/mm2), leading to a 47 repaired motor cortex with layered cortical structures. Moreover, NeuroD1-converted 48 neurons not only form functional neural circuits but also rescue motor and memory 49 deficits after ischemic injury. Our results establish the proof-of-principle that a highly 50 efficient in situ astrocyte-to-neuron conversion approach provides a novel treatment for 51 neurological disorders that are in need of new neurons. 52 row). Interestingly, some NeuroD1 AAV-infected astrocytes were clearly captured in a 128 transitional stage toward neurons, showing co-immunostaining of both NeuN and GFAP 129 (Fig. 1g, bottom row). Remarkably, using our AAV Cre-FLEX system, we detected a 130 large number of NeuroD1-converted neurons in the injured mouse cortex (Fig. 1h, i), 131 which was not possible using the other viruses we had tried. 132 133
Schizophrenia (SZ) is a devastating brain disease that affect about 1% of world population. Among the top genetic associations, zinc finger protein 804A (ZNF804A) gene encodes a zinc finger protein, associated with SZ and biolar disorder (BD). Copy number variants (CNVs) of ZNF804A have been observed in patients with autism spectrum disorders (ASDs), anxiety disorder, and BD, suggesting that ZNF804A is a dosage sensitive gene for brain function. However, its molecular functions have not been fully determined. Our previous interactomic study revealed that ZNF804A interacts with multiple proteins to control protein translation and neural development. ZNF804A is localized in the cytoplasm and neurites in the human cortex and is expressed in various types of neurons, including pyramidal, dopaminergic, GABAergic, and Purkinje neurons in mouse brain. To further examine the effect of gene dosage of ZNF804A on neurite morphology, both knockdown and overexpression of ZNF804A in primary neuronal cells significantly attenuates dendritic morphology and synaptogenesis. To determine the effectors mediating these phenotypes, interestingly, three binding proteins of ZNF804A, galectin 1 (LGALS1), fasciculation and elongation protein zeta 1 (FEZ1) and ribosomal protein SA (RPSA), show different effects on reversing the deficits. LGALS1 and FEZ1 stimulate neurite outgrowth at basal level but RPSA shows no effect. Intriguingly, FEZ1 and RPSA but not LGALS1, can ameliorate ZNF804A-mediated dendritic abnormalities. Thus, our results uncover a critical post-mitotic role of ZNF804A in neurite and synaptic development relevant for neurodevelopmental pathologies.
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