Abstract
The gene CUG-BP, Elav-like factor 6 (CELF6) appears to be important for proper functioning of neurocircuitry responsible for behavioral output. We previously discovered that polymorphisms in or near CELF6 may be associated with autism spectrum disorder (ASD) in humans and that the deletion of this gene in mice results in a partial ASD-like phenotype. Here, to begin to understand which circuits might mediate these behavioral disruptions, we sought to establish in what structures, with what abundance, and at which ages Celf6 protein is present in the mouse brain. Using both a knockout-validated antibody to Celf6 and a novel transgenic mouse line, we characterized Celf6 expression in the mouse brain across development. Celf6 gene products were present early in neurodevelopment and in adulthood. The greatest protein expression was observed in distinct nuclei of the diencephalon and neuromodulatory cell populations of the midbrain and hindbrain, with clear expression in dopaminergic, noradrenergic, histaminergic, serotonergic and cholinergic populations, and a variety of presumptive peptidergic cells of the hypothalamus. These results suggest that disruption of Celf6 expression in hypothalamic nuclei may impact a variety of behaviors downstream of neuropeptide activity, while disruption in neuromodulatory transmitter expressing areas such as the ventral tegmental area, substantia nigra, raphe nuclei and locus coeruleus may have far-reaching influences on overall brain activity.
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Abbreviations
- 10N:
-
Dorsal motor nucleus of vagus
- 3N:
-
Oculomotor nucleus
- A12:
-
A12 dopamine cells
- A13:
-
A13 dopamine cells
- A14:
-
A14 dopamine cells
- Acb:
-
Accumbens nucleus
- AcbC:
-
Accumbens nucleus, core
- AcbSh:
-
Accumbens nucleus, shell
- AHA:
-
Anterior hypothalamic area, anterior part
- Amb:
-
Ambiguus nucleus
- Arc:
-
Arcuate hypothalamic nucleus
- Au1:
-
Primary auditory cortex
- AuD:
-
Secondary auditory cortex, dorsal area
- AuV:
-
Secondary auditory cortex, ventral area
- CP:
-
Caudoputamen (striatum)
- DM:
-
Dorsomedial hypothalamic nucleus
- DR:
-
Dorsal raphe nucleus
- EW:
-
Edinger–Westphal nucleus
- GP:
-
Globus pallidus
- HDB:
-
Nucleus of the horizontal limb of the diagonal band
- IO:
-
Inferior olivary nucleus
- LC:
-
Locus coeruleus
- LDTg:
-
Laterodorsal tegmental nucleus
- LH:
-
Lateral hypothalamic area
- LHb:
-
Lateral habenular nucleus
- LMol:
-
Lacunosum moleculare layer of the hippocampus
- LPO:
-
Lateral preoptic area
- LRt:
-
Lateral reticular nucleus
- MHb:
-
Medial habenular nucleus
- MnR:
-
Median raphe nucleus
- MPA:
-
Medial preoptic area
- MS:
-
Medial septal nucleus
- MTu:
-
Medial tuberal nucleus
- MVeMC:
-
Medial vestibular nucleus, magnocellular part
- Pa:
-
Paraventricular hypothalamic nucleus
- PAG:
-
Periaqueductal gray
- PDTg:
-
Posterodorsal tegmental nucleus
- Pe:
-
Periventricular hypothalamic nucleus
- PnC:
-
Pontine reticular nucleus, caudal part
- PTg:
-
Pedunculotegmental nucleus
- PV:
-
Paraventricular thalamic nucleus
- Rad:
-
Radiatum layer of the hippocampus
- RMg:
-
Raphe magnus nucleus
- RO:
-
Raphe obscurus nucleus
- RPa:
-
Raphe pallidus nucleus
- SI:
-
Substantia innominata
- SIB:
-
Substantia innominata, basal part
- SNc:
-
Substantia nigra, compact part
- SO:
-
Supraoptic nucleus
- TeA:
-
Temporal association cortex
- V1B:
-
Primary visual cortex, binocular area
- VDB:
-
Nucleus of the vertical limb of the diagonal band
- VLPO:
-
Ventrolateral preoptic nucleus
- VTA:
-
Ventral tegmental area
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Acknowledgments
The authors would like to thank Arthur Loewy, Paul Gray, Nathaniel Heintz, and Cristina de Guzman Strong for equipment, reagents and discussion. We would also like to thank Heifen Feng, Juliet Zhang, and Afua Akuffo for technical assistance. Funding was provided by R21MH099798, DA038458-01, R00NS067239 to JDD, and an ACE network grant R01MH100027.
Conflict of interest
None of the authors has any established or potential conflict of interest to declare in relation with the current work.
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Maloney, S.E., Khangura, E. & Dougherty, J.D. The RNA-binding protein Celf6 is highly expressed in diencephalic nuclei and neuromodulatory cell populations of the mouse brain. Brain Struct Funct 221, 1809–1831 (2016). https://doi.org/10.1007/s00429-015-1005-z
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DOI: https://doi.org/10.1007/s00429-015-1005-z