No abstract

Factors that regulate terminal arbor size of substantia nigra pars compacta (SNpc) neurons during development and after injury are not well understood. This study examined the role of dopamine receptors in regulating arbor size. Terminal arbors were examined in mice with targeted deletion of the D1 or D2 dopamine receptor [D1(Ϫ/Ϫ) and D2(Ϫ/Ϫ) mice, respectively]. Terminal trees were also examined after treatment with receptor blockers and after partial SNpc lesions. Immunohistochemistry was performed, and the number of SNpc neurons and dopaminergic terminals in the striatum was estimated. The number of dopaminergic SNpc neurons were reduced in D1(Ϫ/Ϫ) and D2(Ϫ/Ϫ) mice. Density of dopaminergic terminals was unchanged in D1(Ϫ/Ϫ) mice and increased in D2 (Ϫ/Ϫ) mice. Steady-state striatal DA and DOPAC levels revealed that dopamine activity was enhanced in D2(Ϫ/Ϫ) mice but reduced in D1(Ϫ/Ϫ) mice.Two months after partial SNpc lesions, striatal terminal density was normal in both wild-type and D1(Ϫ/Ϫ) mice but reduced in D2(Ϫ/Ϫ) mice. Administration of DA receptor antagonists resulted in larger terminal arbors in D1(Ϫ/Ϫ) and wildtype mice, whereas D2(Ϫ/Ϫ) mice showed no change in terminal density.Functional blockade of the D2R during development or in the adult brain results in increased axonal sprouting. Partial SNpc lesions resulted in compensatory sprouting, only in mice with functional D2R. These results suggest that individual dopaminergic axons in D2(Ϫ/Ϫ) mice have reached maximal arbor size. We conclude that the D2 receptor may play a role in modulating the extent of the terminal arbor of SNpc neurons. Key words: regeneration; dopamine receptors; sprouting; axonal arbor; dopamine antagonists; D1 receptor knock-out; D2 receptor knock-out; 6-OHDA lesionsThere is now substantial evidence that neurons in the adult CNS can form new synapses, neurites, and branches (Raisman and Field, 1973;Fagan and Gage, 1994;Frotscher et al., 1997). After injury in the striatum or substantia nigra pars compacta (SNpc), a number of compensatory changes occur that suggest regenerative processes are present. These changes include the formation of new synaptic terminals, growth-cone structures (indicating axonal sprouting), neurite formation, increased number of tyrosine hydroxylase-immunoreactive (TH-IR) hypertrophic fibers penetrating the striatum, the upregulated expression of factors that support neurite outgrowth and cell survival, and increased dopamine levels (Zigmond et al

Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1-chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.Smchd1 | epigenetic control | clustered protocadherins | Ctcf

No abstract

Attempts to repair the central nervous system damaged as a result of trauma or disease will depend on the ability to restore the appropriate neuronal connectivity. This will rely on establishing appropriate chemical and physical environments for supporting neural cells and their processes and in this regard, engineering of biomaterials is of increasing interest. It will be important to understand how cells behave on these biomaterials in vitro, prior to future in vivo application. We reveal that modification of 3-dimensional (3D) electrospun poly-epsilon-caprolactone (PCL) nanofiber scaffolds by fiber alignment and aminolysation is superior to classical 2-dimensional (2D) culture-ware in promoting in vitro proliferation and differentiation of cortical cells. Many studies have examined the importance of exogenous soluble factors to promote cell fate specification. Here, we demonstrate that tethering the neurotrophin, brain-derived neurotrophic factor (BDNF), onto modified nanofibers is superior to culturing in the presence of soluble BDNF. Functional immobilization of BDNF to polymer nanofibers enhances neural stem cell (NSC) proliferation and directs cell fate toward neuronal and oligodendrocyte specification, essential for neural tissue repair. These findings indicate that modified PCL nanofibrous 3D scaffolds are capable of supporting NSCs and their derivatives and may present a new avenue for encouraging neural repair in the future.