Direct and Indirect Regulation of Spinal Cord Ia Afferent Terminal Formation by the γ-Protocadherins

The Pcdh-γ gene cluster encodes 22 protocadherin adhesion molecules that interact as homophilic multimers and critically regulate synaptogenesis and apoptosis of interneurons in the developing spinal cord. Unlike interneurons, the two primary components of the monosynaptic stretch reflex circuit, dorsal root ganglion sensory neurons and ventral motor neurons (MNs), do not undergo excessive apoptosis in Pcdh-γdel/del null mutants, which die shortly after birth. However, as we show here, mutants exhibit severely disorganized Ia proprioceptive afferent terminals in the ventral horn. In contrast to the fine net-like pattern observed in wild-type mice, central Ia terminals in Pcdh-γ mutants appear clumped, and fill the space between individual MNs; quantitative analysis shows a ~2.5-fold increase in the area of terminals. Concomitant with this, there is a 70% loss of the collaterals that Ia afferents extend to ventral interneurons (vINs), many of which undergo apoptosis in the mutants. The Ia afferent phenotype is ameliorated, though not entirely rescued, when apoptosis is blocked in Pcdh-γ null mice by introduction of a Bax null allele. This indicates that loss of vINs, which act as collateral Ia afferent targets, contributes to the disorganization of terminals on motor pools. Restricted mutation of the Pcdh-γ cluster using conditional mutants and multiple Cre transgenic lines (Wnt1-Cre for sensory neurons; Pax2-Cre for vINs; Hb9-Cre for MNs) also revealed a direct requirement for the γ-Pcdhs in Ia neurons and vINs, but not in MNs themselves. Together, these genetic manipulations indicate that the γ-Pcdhs are required for the formation of the Ia afferent circuit in two ways: First, they control the survival of vINs that act as collateral Ia targets; and second, they provide a homophilic molecular cue between Ia afferents and target vINs

Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity

SummaryGrowth of a properly complex dendrite arbor is a key step in neuronal differentiation and a prerequisite for neural circuit formation. Diverse cell surface molecules, such as the clustered protocadherins (Pcdhs), have long been proposed to regulate circuit formation through specific cell-cell interactions. Here, using transgenic and conditional knockout mice to manipulate γ-Pcdh repertoire in the cerebral cortex, we show that the complexity of a neuron’s dendritic arbor is determined by homophilic interactions with other cells. Neurons expressing only one of the 22 γ-Pcdhs can exhibit either exuberant or minimal dendrite complexity, depending only on whether surrounding cells express the same isoform. Furthermore, loss of astrocytic γ-Pcdhs, or disruption of astrocyte-neuron homophilic matching, reduces dendrite complexity cell non-autonomously. Our data indicate that γ-Pcdhs act locally to promote dendrite arborization via homophilic matching, and they confirm that connectivity in vivo depends on molecular interactions between neurons and between neurons and astrocytes

Relaxation oscillations, stability, and cavity feedback in a superradiant Raman laser

We experimentally study the relaxation oscillations and amplitude stability properties of an optical laser operating deep into the bad-cavity regime using a laser-cooled $^{87}$Rb Raman laser. By combining measurements of the laser light field with nondemolition measurements of the atomic populations, we infer the response of the gain medium represented by a collective atomic Bloch vector. The results are qualitatively explained with a simple model. Measurements and theory are extended to include the effect of intermediate repumping states on the closed-loop stability of the oscillator and the role of cavity feedback on stabilizing or enhancing relaxation oscillations. This experimental study of the stability of an optical laser operating deep into the bad-cavity regime will guide future development of superradiant lasers with ultranarrow linewidths.Comment: 9 pages, 6 figure

General Formalism for Evaluating the Impact of Phase Noise on Bloch Vector Rotations

Quantum manipulation protocols for quantum sensors and quantum computation often require many single qubit rotations. However, the impact of phase noise in the field that performs the qubit rotations is often neglected or treated only for special cases. We present a general framework for calculating the impact of phase noise on the state of a qubit, as described by its equivalent Bloch vector. The analysis applies to any Bloch vector orientation, and any rotation axis azimuthal angle for both a single pulse, and pulse sequences. Experimental examples are presented for several special cases. We apply the analysis to commonly used composite $\pi$-pulse sequences: CORPSE, SCROFULOUS, and BB1, used to suppress static amplitude and detuning errors, and also to spin echo sequences. We expect the formalism presented will help guide the development and evaluation of future quantum manipulation protocols.Comment: 12 pages, 6 figures, submitted to PR

A putative ariadne-like E3 ubiquitin ligase (PAUL) that interacts with the muscle-specific kinase (MuSK).

Formation of the postsynaptic membrane at the skeletal neuromuscular junction (NMJ) requires activation of the muscle-specific receptor tyrosine kinase (MuSK). Few intracellular mediators or modulators of MuSK actions are known. E3 ubiquitin ligases may serve this role, because activities of several receptor tyrosine kinases, G-protein-coupled receptors and channels are modulated by ubiquitination. Here, we report identification of a putative Ariadne-like ubiquitin ligase (PAUL) that binds to the cytoplasmic domain of MuSK. PAUL is expressed in numerous tissues of developing and adult mice, and is present at NMJs in muscle fibers but is not confined to them.Peer reviewe

Distinct Retinohypothalamic Innervation Patterns Predict the Developmental Emergence of Species-typical Circadian Phase Preference in Nocturnal Norway Rats and Diurnal Nile Grass Rats

How does the brain develop differently to support nocturnality in some mammals, but diurnality in others? To answer this question, one might look to the suprachiasmatic nucleus (SCN), which is entrained by light via the retinohypothalamic tract (RHT). However, because the SCN is more active during the day in all mammals studied thus far, it alone cannot determine circadian phase preference. In adult Norway rats (Rattus norvegicus), which are nocturnal, the RHT also projects to the ventral subparaventricular zone (vSPVZ), an adjacent region that expresses an in-phase pattern of SCN-vSPVZ neuronal activity. In contrast, in adult Nile grass rats (Arvicanthis niloticus), which are diurnal, an anti-phase pattern of SCN-vSPVZ neuronal activity is expressed. We hypothesized that these species differences result in part from a weak or absent RHT-to-vSPVZ projection in grass rats. Here, using a developmental comparative approach, we assessed species differences in behavior, hypothalamic activity, and RHT anatomy. We report that a robust retina-to-vSPVZ projection develops in Norway rats around the end of the second postnatal week when nocturnal wakefulness and the in-phase pattern of neuronal activity emerge. In grass rats, however, such a projection does not develop and the emergence of the anti-phase pattern during the second postnatal week is accompanied by increased diurnal wakefulness. When considered within the context of previously published reports on RHT projections in a variety of species, the current findings suggest that how and when the retina connects to the hypothalamus differentially shapes brain and behavior to produce animals that occupy opposing temporal niches

Essential role for ALCAM gene silencing in megakaryocytic differentiation of K562 cells

<p>Abstract</p> <p>Background</p> <p>Activated leukocyte cell adhesion molecule (ALCAM/CD166) is expressed by hematopoietic stem cells. However, its role in hematopoietic differentiation has not previously been defined.</p> <p>Results</p> <p>In this study, we show that ALCAM expression is silenced in erythromegakaryocytic progenitor cell lines. In agreement with this finding, the ALCAM promoter is occupied by GATA-1 <it>in vivo</it>, and a cognate motif at -850 inhibited promoter activity in K562 and MEG-01 cells. Gain-of-function studies showed that ALCAM clusters K562 cells in a process that requires PKC. Induction of megakaryocytic differentiation in K562 clones expressing ALCAM activated PKC-δ and triggered apoptosis.</p> <p>Conclusions</p> <p>There is a lineage-specific silencing of ALCAM in bi-potential erythromegakaryocytic progenitor cell lines. Marked apoptosis of ALCAM-expressing K562 clones treated with PMA suggests that aberrant ALCAM expression in erythromegakaryocytic progenitors may contribute to megakaryocytopenia.</p