The p75 neurotrophin receptor is required for the survival of neuronal progenitors and normal formation of the basal forebrain, striatum, thalamus and neocortex

Meier, Sonja; Alfonsi, Fabienne; Kurniawan, Nyoman D.; Milne, Michael R.; Kasherman, Maria; Delogu, Alessio; Piper, Michael; Coulson, Elizabeth J.

doi:10.1242/dev.181933

Cited by 25 publications

(17 citation statements)

References 56 publications

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“…TrkC deficiency may lead to activation of the neurotrophic receptor p75 NTR . This receptor regulates many aspects in the developing brain such as cell survival, neurite outgrowth, and, paradoxically, apoptosis, the opposite function that induces cell death (Bibel et al, 1999 ; Naska et al, 2010 ; Meier et al, 2019 ). We found that p75 NTR is expressed in the early development of the opossum cerebellum.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of TrkC Receptors Increases Dendritic Arborization of Purkinje Cells in the Developing Cerebellum of the Opossum, Monodelphis domestica

et al. 2020

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In therian mammals, the cerebellum is one of the late developing structures in the brain. Specifically, the proliferation of cerebellar granule cells occurs after birth, and even in humans, the generation of these cells continues during the first year of life. The main difference between marsupials and eutherians is that the majority of the brain structures in marsupials develop after birth. Herein, we report that in the newborn laboratory opossum (Monodelphis domestica), the cerebellar primordium is distinguishable in Nisslstained sections. Additionally, bromodeoxyuridine birthdating experiments revealed that the first neurons form the deep cerebellar nuclei (DCN) and Purkinje cells, and are generated within postnatal days (P) 1 and 5. Three weeks after birth, progenitors of granule cells in the external germinal layer (EGL) proliferate, producing granule cells. These progenitor cells persist for a long time, approximately 5 months. Furthermore, to study the effects of neurotrophic tropomyosin receptor kinase C (TrkC) during cerebellar development, cells were obtained from P3 opossums and cultured for 8 days. We found that TrkC downregulation stimulates dendritic branching of Purkinje neurons, which was surprising. The number of dendritic branches was higher in Purkinje cells transfected with the shRNA TrkC plasmid. However, there was no morphological change in the number of dendritic branches of granule cells transfected with either control or shRNA TrkC plasmids. We suggest that inhibition of TrkC activity enables NT3 binding to the neurotrophic receptor p75 NTR that promotes dendritic arborization of Purkinje cells. This effect of TrkC receptors on dendritic branching is cell type specific, which could be explained by the strong expression of TrkC in Purkinje cells but not in granule cells. The data indicate a new role for TrkC receptors in Monodelphis opossum.

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Section: Discussionmentioning

confidence: 99%

Downregulation of TrkC Receptors Increases Dendritic Arborization of Purkinje Cells in the Developing Cerebellum of the Opossum, Monodelphis domestica

et al. 2020

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“…For instance, the use of an Emx1 cre driver would enable the removal of Nsd1 from neural progenitor cells within the dorsal telencephalon from E9.5 . Another option would be to use a nestin cre driver to delete the Nsd1 gene from all neural stem cells from E10.5 . In this way, Nsd1 function in brain development and function could be assayed in isolation from the gastrulation deficits that presumably contribute to the embryonic lethality of null mutants .…”

Section: Discussionmentioning

confidence: 99%

Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1

Oishi

Zalucki

Vega

et al. 2020

Genes Brain and Behavior

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Sotos syndrome is a developmental disorder characterized by a suite of clinical features. In children, the three cardinal features of Sotos syndrome are a characteristic facial appearance, learning disability and overgrowth (height and/or head circumference > 2 SDs above average). These features are also evident in adults with this syndrome. Over 90% of Sotos syndrome patients are haploinsufficient for the gene encoding nuclear receptor‐binding Su(var)3‐9, Enhancer‐of‐zesteand Trithorax domain‐containing protein 1 (NSD1). NSD1 is a histone methyltransferase that catalyzes the methylation of lysine residue 36 on histone H3. However, although the symptomology of Sotos syndrome is well established, many aspects of NSD1 biology remain unknown. Here, we assessed the expression of Nsd1 within the mouse brain, and showed a predominantly neuronal pattern of expression for this histone‐modifying factor. We also generated a mouse strain lacking one allele of Nsd1 and analyzed morphological and behavioral characteristics in these mice, showing behavioral characteristics reminiscent of some of the deficits seen in Sotos syndrome patients.

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“…For instance, the use of an Emx1 cre driver would enable the removal of Nsd1 from neural progenitor cells within the dorsal telencephalon from E9.5 (Zhang et al, 2019). Another option would be to use a nestin cre driver to delete the Nsd1 gene from all neural stem cells from E10.5 (Meier et al, 2019). In this way, Nsd1 function in brain development and function could be assayed in isolation from the gastrulation deficits that presumably contribute to the embryonic lethality of null mutants (Rayasam et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying malformations of cortical development

Oishi¹

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Nuclear Factor One X (NFIX) haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to the enlarged head circumference and intellectual disability in these patients remains undefined. Here, we used Nfix heterozygous mice as a model to investigate these aspects of Malan syndrome. Volumetric magnetic resonance imaging (MRI) was used to calculate the volumes of 20 brain sub regions. Diffusion tensor MRI was used to perform tractography-based analyses of the corpus callosum, hippocampal commissure, and anterior commissure, as well as structural connectome mapping of the whole brain. Immunohistochemistry examined the neocortical cellular populations. Two behavioural assays were performed, including the active place avoidance task to assess spatial navigation and learning and memory function, and the 3-chambered sociability task to examine social behaviour. Adult Nfix+/-mice exhibit significantly increased brain volume (megalencephaly) compared to wildtypes, with the cerebral cortex showing the highest increase. Moreover, all three forebrain commissures, in particular the anterior commissure, revealed significantly reduced fractional anisotropy, axial and radial diffusivity, and tract density intensity. Structural connectome analyses revealed aberrant connectivity between many crucial brain regions. Finally, Nfix+/-mice exhibit behavioural deficits that model intellectual disability. Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit.

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The p75 neurotrophin receptor is required for the survival of neuronal progenitors and normal formation of the basal forebrain, striatum, thalamus and neocortex

Cited by 25 publications

References 56 publications

Downregulation of TrkC Receptors Increases Dendritic Arborization of Purkinje Cells in the Developing Cerebellum of the Opossum, Monodelphis domestica

Downregulation of TrkC Receptors Increases Dendritic Arborization of Purkinje Cells in the Developing Cerebellum of the Opossum, Monodelphis domestica

Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1

Molecular mechanisms underlying malformations of cortical development

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