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The RNA-binding protein Celf6 is highly expressed in diencephalic nuclei and neuromodulatory cell populations of the mouse brain

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.

Author information

Correspondence to Joseph D. Dougherty.

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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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Keywords

  • Celf6
  • Neuromodulatory
  • Diencephalon
  • Development
  • Protein expression
  • Immunohistochemistry