DCC is required for the tangential migration of noradrenergic neurons in locus coeruleus of mouse brain

Shi, Ming; Guo, Chao; Dai, Jinxia; Ding, Yu

doi:10.1016/j.mcn.2008.07.023

Cited by 23 publications

(25 citation statements)

References 63 publications

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“…Norepinephrine innervation to the mPFC matures by the second postnatal week in the rodent (Levitt and Moore, 1979). Nevertheless, we cannot completely rule out the potential involvement of the norepinephrine system in the dcc heterozygous phenotypes because norepinephrine neurons in the locus ceruleus express DCC (Shi et al, 2008).…”

Section: Discussionmentioning

confidence: 92%

The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry

Manitt¹,

Mimee²,

Eng³

et al. 2011

Journal of Neuroscience

117

182

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Netrins are guidance cues involved in neural connectivity. We have shown that the netrin-1 receptor DCC (deleted in colorectal cancer) is involved in the functional organization of the mesocorticolimbic dopamine (DA) system. Adult mice with a heterozygous loss-of-function mutation in dcc exhibit changes in indexes of DA function, including DA-related behaviors. These phenotypes are only observed after puberty, a critical period in the maturation of the mesocortical DA projection. Here, we examined whether dcc heterozygous mice exhibit structural changes in medial prefrontal cortex (mPFC) DA synaptic connectivity, before and after puberty. Stereological counts of tyrosine-hydroxylase (TH)-positive varicosities were increased in the cingulate 1 and prelimbic regions of the pregenual mPFC. dcc heterozygous mice also exhibited alterations in the size, complexity, and dendritic spine density of mPFC layer V pyramidal neuron basilar dendritic arbors. Remarkably, these presynaptic and postsynaptic partner phenotypes were not observed in juvenile mice, suggesting that DCC selectively influences the extensive branching and synaptic differentiation that occurs in the maturing mPFC DA circuit at puberty. Immunolabeling experiments in wild-type mice demonstrated that DCC is segregated to TH-positive fibers innervating the nucleus accumbens, with only scarce DCC labeling in mPFC TH-positive fibers. Netrin had an inverted target expression pattern. Thus, DCC-mediated netrin-1 signaling may influence the formation/maintenance of mesocorticolimbic DA topography. In support of this, we report that dcc heterozygous mice exhibit a twofold increase in the density of mPFC DCC/TH-positive varicosities. Our results implicate DCC-mediated netrin-1 signaling in the establishment of mPFC DA circuitry during puberty.

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Section: Discussionmentioning

confidence: 92%

The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry

Manitt¹,

Mimee²,

Eng³

et al. 2011

Journal of Neuroscience

117

182

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“…Sections were processed for TH and BrdU double immunostaining (see below) to localize BrdU-positive cells in the LC. X-gal staining and TUNEL staining of frozen sections were performed as described previously (Shi et al, 2008;Zheng et al, 2009). …”

Section: Wnt1-cre En1mentioning

confidence: 99%

“…Whole mount and section in situ hybridization were performed as previously described (Shi et al, 2008;Shi et al, 2010). The following mouse antisense RNA probes were used: c-Ret (Ohsawa et al, 2005), Dbh , Fgf8 (Wassarman et al, 1997), Gbx2 (Liu and Joyner, 2001b), Hes1 (Lee et al, 2005), Hes5 , Ngn1, Ngn2 (Sommer et al, 1996), Otx2 (MartinezBarbera et al, 2001), Phox2a (Tiveron et al, 1996) and Phox2b (Pattyn et al, 1997).…”

Section: In Situ Hybridization and Immunostainingmentioning

confidence: 99%

Notch-Rbpj signaling is required for the development of noradrenergic neurons in mouse locus coeruleus

Shi

Zheng

et al. 2012

Journal of Cell Science

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SummaryThe locus coeruleus (LC) is the main source of noradrenaline in the brain and is implicated in a broad spectrum of physiological and behavioral processes. However, genetic pathways controlling the development of noradrenergic neurons in the mammalian brain are largely unknown. We report here that Rbpj, a key nuclear effector in the Notch signaling pathway, plays an essential role in LC neuron development in the mouse. Conditional inactivation of Rbpj in the dorsal rhombomere (r) 1, where LC neurons are born, resulted in a dramatic increase in the number of Phox2a-and Phox2b-expressing early-differentiating LC neurons, and dopamine-b-hydroxylase-and tyrosine-hydroxylase-expressing late-differentiating LC neurons. In contrast, other neuronal populations derived from the dorsal r1 were either reduced or unchanged. In addition, a drastic upregulation of Ascl1, an essential factor for noradrenergic neurogenesis, was observed in dorsal r1 of conditional knockout mice. Through genomic sequence analysis and EMSA and ChIP assays, a conserved Rbpjbinding motif was identified within the Ascl1 promoter. A luciferase reporter assay revealed that Rbpj per se could induce Ascl1 transactivation but this effect was counteracted by its downstream-targeted gene Hes1. Moreover, our in vitro gene transfection and in ovo electroporation assays showed that Rbpj upregulated Ascl1 expression when Hes1 expression was knocked down, although it also exerted a repressive effect on Ascl1 expression in the presence of Hes1. Thus, our results provide the first evidence that Rbpj functions as a key modulator of LC neuron development by regulating Ascl1 expression directly, and indirectly through its target gene Hes1.

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“…: NM_013864; forward: 5 0 -CTATCTCGGTCTCGCACAG CA-3 0 , reverse: 5 0 -TTCAGAGAGGCCTGACACATC-3 0 ), and then subcloned into pGEM-T vector (Promega, Madison, WI, USA). Digoxygenin-labeled Ndrg2 anti-sense riboprobe was synthesized and used for in situ hybridization on brain sections as described previously (Shi et al 2008). The uniqueness of Ndrg2 probe was confirmed by the NCBI Blast search program (http://www.ncbi.nlm.nih.gov/BLA ST/Blast.cgi), that is, the probe is specific to Ndrg2 gene and has no homologous sequences with other numbers (e.g.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

“…In situ hybridization and immunohistochemistry double labeling Double labeling of in situ hybridization and immunohistochemistry was carried out as described previously (Liu et al , 2010Shi et al 2008) with some modifications. In brief, in situ hybridization of Ndrg2 was first performed as described above but without proteinase K treatment.…”

Section: Brdu Administrationmentioning

confidence: 99%

Ndrg2 expression in neurogenic germinal zones of embryonic and postnatal mouse brain

et al. 2011

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N-myc downstream-regulated gene 2 (Ndrg2) is well-known for its involvement in tumor cell proliferation and differentiation. This promotes us to investigate whether Ndrg2 also functions in neurogenesis, during which some cellular events are similar to that of tumorigenesis. As the first step in exploring the role of Ndrg2 in neurogenesis, here we performed in situ hybridization with a Ndrg2-specific probe to examine Ndrg2 mRNA expression in neurogenic germinal zones of embryonic and postnatal mouse brain. Our results showed that Ndrg2 mRNA was highly expressed in the cortical ventricular zone at various embryonic stages. At postnatal stages, Ndrg2 transcripts were downregulated but still abundant in the subventricular zone of lateral ventricle and subgranular zone of hippocampal dentate gyrus where persistent neurogenesis occurs in the mammalian brain throughout life. Double staining of Ndrg2 mRNA with proliferation markers BrdU and Ki67, or with neural progenitor cell marker Nestin revealed that Ndrg2 was expressed in proliferating precursor cells. Thus, abundant expression of Ndrg2 mRNA in neural proliferating cell populations indicates an important role of Ndrg2 in neurogenesis of both embryonic and postnatal mouse brain.

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DCC is required for the tangential migration of noradrenergic neurons in locus coeruleus of mouse brain

Cited by 23 publications

References 63 publications

The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry

The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry

Notch-Rbpj signaling is required for the development of noradrenergic neurons in mouse locus coeruleus

Ndrg2 expression in neurogenic germinal zones of embryonic and postnatal mouse brain

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