Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice.

Background: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival.

Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex.

Neurodevelopmental disorders are characterized by alterations in the development of the cerebral cortex, including aberrant changes in the number and function of neural cells. Although neurogenesis is one of the most studied cellular processes in these pathologies, little evidence is known about glial development. Genetic association studies have identified several genes associated with neurodevelopmental disorders.

c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.

The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria.

c-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer's disease.

Background: Growing evidence suggests that the non-receptor tyrosine kinase, c-Abl, plays a significant role in the pathogenesis of Alzheimer's disease (AD). Here, we analyzed the effect of c-Abl on the cognitive performance decline of APPSwe/PSEN1ΔE9 (APP/PS1) mouse model for AD.

Methods: We used the conditional genetic ablation of c-Abl in the brain (c-Abl-KO) and pharmacological treatment with neurotinib, a novel allosteric c-Abl inhibitor with high brain penetrance, imbued in rodent's chow.

The c-Abl/p73 pathway induces neurodegeneration in a Parkinson's disease model.

Parkinson's disease is the second most common neurodegenerative disorder. Although it is clear that dopaminergic neurons degenerate, the underlying molecular mechanisms are still unknown, and thus, successful treatment is still elusive. One pro-apoptotic pathway associated with several neurodegenerative diseases is the tyrosine kinase c-Abl and its target p73.

Consequences of Viral Infection and Cytokine Production During Pregnancy on Brain Development in Offspring.

Infections during pregnancy can seriously damage fetal neurodevelopment by aberrantly activating the maternal immune system, directly impacting fetal neural cells. Increasing evidence suggests that these adverse impacts involve alterations in neural stem cell biology with long-term consequences for offspring, including neurodevelopmental disorders such as autism spectrum disorder, schizophrenia, and cognitive impairment. Here we review how maternal infection with viruses such as Influenza A, Cytomegalovirus, and Zika during pregnancy can affect the brain development of offspring by promoting the release of maternal pro-inflammatory cytokines, triggering neuroinflammation of the fetal brain, and/or directly infecting fetal neural cells.

LAR Receptor Tyrosine Phosphatase Family in Healthy and Diseased Brain.

Protein phosphatases are major regulators of signal transduction and they are involved in key cellular mechanisms such as proliferation, differentiation, and cell survival. Here we focus on one class of protein phosphatases, the type IIA Receptor-type Protein Tyrosine Phosphatases (RPTPs), or LAR-RPTP subfamily. In the last decade, LAR-RPTPs have been demonstrated to have great importance in neurobiology, from neurodevelopment to brain disorders.

The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis.

PTPRD is a receptor protein tyrosine phosphatase that is genetically associated with neurodevelopmental disorders. Here, we asked whether Ptprd mutations cause aberrant neural development by perturbing neurogenesis in the murine cortex. We show that loss of Ptprd causes increases in neurogenic transit-amplifying intermediate progenitor cells and cortical neurons and perturbations in neuronal localization.

A Glo1-Methylglyoxal Pathway that Is Perturbed in Maternal Diabetes Regulates Embryonic and Adult Neural Stem Cell Pools in Murine Offspring.

Maternal diabetes is known to adversely influence brain development in offspring. Here, we provide evidence that this involves the circulating metabolite methylglyoxal, which is increased in diabetes, and its detoxifying enzyme, glyoxalase 1 (Glo1), which when mutated is associated with neurodevelopmental disorders. Specifically, when Glo1 levels were decreased in embryonic mouse cortical neural precursor cells (NPCs), this led to premature neurogenesis and NPC depletion embryonically and long-term alterations in cortical neurons postnatally.

The aPKC-CBP Pathway Regulates Adult Hippocampal Neurogenesis in an Age-Dependent Manner.

While epigenetic modifications have emerged as attractive substrates to integrate environmental changes into the determination of cell identity and function, specific signals that directly activate these epigenetic modifications remain unknown. Here, we examine the role of atypical protein kinase C (aPKC)-mediated Ser436 phosphorylation of CBP, a histone acetyltransferase, in adult hippocampal neurogenesis and memory. Using a knockin mouse strain (CbpS436A) in which the aPKC-CBP pathway is deficient, we observe impaired hippocampal neuronal differentiation, maturation, and memory and diminished binding of CBP to CREB in 6-month-old CbpS436A mice, but not at 3 months of age.

Proneurogenic Ligands Defined by Modeling Developing Cortex Growth Factor Communication Networks.

The neural stem cell decision to self-renew or differentiate is tightly regulated by its microenvironment. Here, we have asked about this microenvironment, focusing on growth factors in the embryonic cortex at a time when it is largely comprised of neural precursor cells (NPCs) and newborn neurons. We show that cortical NPCs secrete factors that promote their maintenance, while cortical neurons secrete factors that promote differentiation.

Transgenic overexpression of Niemann-Pick C2 protein promotes cholesterol gallstone formation in mice.

Background & Aims: Niemann-Pick C2 (NPC2) is a lysosomal protein involved in the egress of low-density lipoprotein-derived cholesterol from lysosomes to other intracellular compartments. NPC2 has been detected in several tissues and is also secreted from the liver into bile. We have previously shown that NPC2-deficient mice fed a lithogenic diet showed reduced biliary cholesterol secretion as well as cholesterol crystal and gallstone formation.

Conditional ablation of p63 indicates that it is essential for embryonic development of the central nervous system.

p63 is a member of the p53 family that regulates the survival of neural precursors in the adult brain. However, the relative importance of p63 in the developing brain is still unclear, since embryonic p63(-/-) mice display no apparent deficits in neural development. Here, we have used a more definitive conditional knockout mouse approach to address this issue, crossing p63(fl/fl) mice to mice carrying a nestin-CreERT2 transgene that drives inducible recombination in neural precursors following tamoxifen treatment.

Ankrd11 is a chromatin regulator involved in autism that is essential for neural development.

Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain.

The Snail transcription factor regulates the numbers of neural precursor cells and newborn neurons throughout mammalian life.

The Snail transcription factor regulates diverse aspects of stem cell biology in organisms ranging from Drosophila to mammals. Here we have asked whether it regulates the biology of neural precursor cells (NPCs) in the forebrain of postnatal and adult mice, taking advantage of a mouse containing a floxed Snail allele (Snailfl/fl mice). We show that when Snail is inducibly ablated in the embryonic cortex, this has long-term consequences for cortical organization.

Neurog1 and Neurog2 control two waves of neuronal differentiation in the piriform cortex.

The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons share a pallial origin, the factors that specify their precise phenotypes are poorly understood.

Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway.

The mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has been implicated in cognitive disorders, might have long-lasting consequences for neural stem cell pools in adult progeny. We show that transient, maternally administered interleukin-6 (IL-6) resulted in an expanded adult forebrain neural precursor pool and perturbed olfactory neurogenesis in offspring months after fetal exposure.

p63 Regulates adult neural precursor and newly born neuron survival to control hippocampal-dependent Behavior.

The molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thus maintain adult neurogenesis, are not well defined. Here, we investigate the role of p63, a p53 family member, in adult NPC function in mice. Conditional ablation of p63 in adult NPCs or p63 haploinsufficiency led to reduced numbers of NPCs and newborn neurons in the neurogenic zones of the hippocampus and lateral ventricles and in the olfactory bulb.

Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation.

Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture.

p73 haploinsufficiency causes tau hyperphosphorylation and tau kinase dysregulation in mouse models of aging and Alzheimer's disease.

Haploinsufficiency for the p53 family member p73 causes behavioral and neuroanatomical correlates of neurodegeneration in aging mice, including the appearance of aberrant phospho-tau-positive aggregates. Here, we show that these aggregates and tau hyperphosphorylation, as well as a generalized dysregulation of the tau kinases GSK3β, c-Abl, and Cdk5, occur in the brains of aged p73+/- mice. To investigate whether p73 haploinsufficiency therefore represents a general risk factor for tau hyperphosphorylation during neurodegeneration, we crossed the p73+/- mice with 2 mouse models of neurodegeneration, TgCRND8+/Ø mice that express human mutant amyloid precursor protein, and Pin1-/- mice.