Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

Rossman, Ian; Lin, Lu-Lu; Morgan, Katherine M.; DiGiovine, Marissa; Buskirk, Elise K. Van; Kamdar, Silky; Millonig, James H.; DiCicco‐Bloom, Emanuel

doi:10.1186/2040-2392-5-9

Cited by 20 publications

(20 citation statements)

References 114 publications

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“…Cerebellar granular neuron cultures from B6/C57 mice at PNDs 5–8 were adapted from previously describe protocols (Rossman et al, ). Briefly, three to six cerebella were cleaned, dissociated by 3‐min treatment with trypsin‐DNase (1% trypsin, 0.1% DNase, Worthington, Lakewood, NJ), and triturated in DNase solution (0.05% in DMEM).…”

Section: Methodsmentioning

confidence: 99%

Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis

Dever

Adham

Thompson

et al. 2015

Developmental Neurobiology

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The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic-helix-loop-helix (bHLH)/PER-ARNT-SIM(PAS) transcription factor superfamily that also mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence suggests that AhR influences the development of many tissues, including the central nervous system. Our previous studies suggest that sustained AhR activation by TCDD and/or AhR deletion disrupts cerebellar granule neuron precursor (GNP) development. In the current study, to determine whether endogenous AhR controls GNP development in a cell autonomous manner, we created a GNP-specific AhR deletion mouse, AhRfx/fx/Math1CRE/+ (AhR CKO). Selective AhR deletion in GNPs produced abnormalities in proliferation and differentiation. Specifically, fewer GNPs were engaged in S-phase, as demonstrated by ~25% reductions in thymidine (in vitro) and BrdU (in vivo) incorporation. Furthermore, total granule neuron numbers in the IGL at PND21 and PND60 were diminished in AhR CKO mice compared to controls. On the other hand, differentiation was enhanced, including ~40% increase in neurite outgrowth and 50% increase in GABARα6 receptor expression in deletion mutants. Our results suggest that AhR activity plays a role in regulating granule neuron number and differentiation, possibly by coordinating this GNP developmental transition. These studies provide novel insights for understanding the normal roles of AhR signaling during cerebellar granule cell neurogenesis, and may have important implications for the effects of environmental factors in cerebellar dysgenesis.

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Section: Methodsmentioning

confidence: 99%

Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis

Dever

Adham

Thompson

et al. 2015

Developmental Neurobiology

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“…Mutations in the En genes affect the ventral mid-hindbrain nuclei, the locus coeruleus (LC) and the raphe nuclei (RN), ultimately resulting in abnormal levels of norepinephrine (NE) and serotonin (5HT) in forebrain and hindbrain areas during development [37][38][39]. Mice with a deletion of the En2 gene from birth (En2 -/-) demonstrate severe cerebellar hypoplasia, reduced Purkinje cell numbers, disruptions in cerebellar patterning and foliation, reduced hippocampal weight, increased dentate gyrus cell turnover, and an anterior shift in the position of the amygdala nuclei [24,33,[40][41][42][43][44][45][46][47][48]. From a behavioral standpoint, juvenile En2 -/mice, compared with wild-type (WT, En2 +/+ ) mice, display impaired social interaction, memory deficits, improper sensory-motor gating, decreased play, reduced social sniffing, reduced aggressiveness, and depression-related behaviors [24,33,41,[43][44][45][46][47].…”

Section: Introductionmentioning

confidence: 99%

Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult Engrailed 2 null mice

Verpeut

DiCicco‐Bloom

Bello

2016

Physiology & Behavior

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Prolonged consumption of ketogenic diets (KD) has reported neuroprotective benefits. Several studies suggest KD interventions could be useful in the management of neurological and developmental disorders. Alterations in the Engrailed (En) genes, specifically Engrailed 2 (En2), have neurodevelopmental consequences and produce autism-related behaviors. The following studies used En2 knockout (KO; En2(-/-)), and wild-type (WT; En2(+/+)), male mice fed either KD (80% fat, 0.1% carbohydrates) or control diet (CD; 10% fat, 70% carbohydrates). The objective was to determine whether a KD fed from weaning at postnatal day (PND) 21 to adulthood (PND 60) would alter brain monoamines concentrations, previously found dysregulated, and improve social outcomes. In WT animals, there was an increase in hypothalamic norepinephrine content in the KD-fed group. However, regional monoamines were not altered in KO mice in KD-fed compared with CD-fed group. In order to determine the effects of juvenile exposure to KD in mice with normal blood ketone levels, separate experiments were conducted in mice removed from the KD or CD and fed standard chow for 2days (PND 62). In a three-chamber social test with a novel mouse, KO mice previously exposed to the KD displayed similar social and self-grooming behaviors compared with the WT group. Groups previously exposed to a KD, regardless of genotype, had more c-Fos-positive cells in the cingulate cortex, lateral septal nuclei, and anterior bed nucleus of the stria terminalis. In the novel object condition, KO mice previously exposed to KD had similar behavioral responses and pattern of c-Fos immunoreactivity compared with the WT group. Thus, juvenile exposure to KD resulted in short-term consequences of improving social interactions and appropriate exploratory behaviors in a mouse model that displays autism-related behaviors. Such findings further our understanding of metabolic-based therapies for neurological and developmental disorders.

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“…These findings led to a focus on the contribution of the cerebellum to nonmotor cognitive functions [Fatemi et al, ; Strick, Dum, & Fiez, ]. The identification of autism risk genes, such as En2 (Engrailed homeobox 2) [James, Shpyleva, Melnyk, Pavliv, & Pogribny, ] and Met (Met proto‐oncogene) [Abrahams & Geschwind, ; Rossman et al, ; Schaaf & Zoghbi, ] known to be involved in the development of the cerebellum and hindbrain suggested that the emphasis should shift from theories espousing localized dysfunction of the cerebellum to the investigation of mechanisms of hind brain and forebrain development and of the widely distributed circuitry interconnecting them [Fatemi et al, ; Rogers et al, ]. These mechanisms are not yet well delineated.…”

Section: Introductionmentioning

confidence: 99%

Visual and Vestibular Induced Eye Movements in Verbal Children and Adults with Autism

2015

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This study investigated several types of eye movements that rely on the function of brainstem-cerebellar pathways specifically (vestibular-ocular reflexes) or on widely distributed pathways of the brain (horizontal pursuit and saccade eye movements). Although eye movements that rely on higher brain regions have been studies fairly extensively in autism, eye movements dependent on brainstem and cerebellum have not. This study involved 79 individuals with autism and 62 typical controls aged 5 to 52 years with IQ scores above 70. No differences between the autism and control groups were present on the measures of vestibular ocular reflexes, or on saccade velocity or accuracy. The autism group was significantly slower to initiate saccades, which was most prominent in the 8-18 year old age range. These findings provide the most substantial evidence to date of the functional integrity of brainstem and cerebellar pathways in autism, suggesting that the histopathological abnormalities described in these structures may not be associated with intrinsic dysfunction but rather reflect developmental alterations related to forebrain cortical systems formation. The increase in saccade latency adds to the substantial evidence of altered function and maturation of cortical systems in autism. Objective This study assessed the functionality of vestibular, pursuit and saccade circuitry in autism across a wide age range. Methods Subjects were 79 individuals with autism (AUT) and 62 controls (CON) aged 5 to 52 years with IQ scores > 70. For vestibular testing, earth-vertical axis rotation was performed in darkness and in a lighted visual surround with a fixation target. Ocular motor testing included assessment of horizontal saccades and horizontal smooth pursuit. Results No between-group differences were found in vestibular reflexes or in mean saccade velocity or accuracy. Saccade latency was increased in the AUT group with significant age-related effects in the 8-18 year old subgroups. There was a trend toward decreased pursuit gain without age effects. Conclusions Normal vestibular-induced eye movements and normal saccade accuracy and velocity provide the most substantial evidence to date of the functional integrity of brainstem and cerebellar pathways in autism, suggesting that the histopathological abnormalities described in these structures may not be associated with intrinsic dysfunction but rather reflect developmental alterations related to forebrain cortical systems formation. Increased saccade latency with age effects adds to the extensive existing evidence of altered function and maturation of cortical systems in autism.

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Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

Cited by 20 publications

References 114 publications

Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis

Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis

Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult Engrailed 2 null mice

Visual and Vestibular Induced Eye Movements in Verbal Children and Adults with Autism

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