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PubMed2005

Relationship between emotional numbing and arousal symptoms in American women of Japanese descent who experienced interpersonal victimization.

In recent years, studies of veterans and others who experienced various types of trauma have found a strong relationship between emotional numbing and arousal symptoms, challenging the current DSM-IV diagnostic criteria, which combines emotional numbing and avoidance symptoms in a single criterion. In this paper, we investigate emotional numbing symptoms in a community-based random sample of women of Japanese descent who had experienced interpersonal victimization, such as childhood abuse, intimate partner violence, and violence perpetrated by non-intimates (n = 202). Controlling for age, place of birth, and timing and severity of victimization, emotional numbing symptom counts were associated more strongly with arousal than avoidance symptoms, consistent with previous studies of veterans and assaulted women. In addition, emotional numbing symptom counts were significantly associated with age and, to a lesser degree, country of birth. Implications for research and practice are discussed.

Adolescent↗
PubMed1996

Control of daughter cell fates during asymmetric division: interaction of Numb and Notch.

During development of the Drosophila peripheral nervous system, a sensory organ precursor (SOP) cell undergoes rounds of asymmetric divisions to generate four distinct cells of a sensory organ. Numb, a membrane-associated protein, is asymmetrically segregated into one daughter cell during SOP division and acts as an inherited determinant of cell fate. Here, we show that Notch, a transmembrane receptor mediated cell-cell communication, functions as a binary switch in cell fate specification during asymmetric divisions of the SOP and its daughter cells in embryogenesis. Moreover, numb negatively regulates Notch, probably through direct protein-protein interaction that requires the phosphotyrosine-binding (PTB) domain of Numb and either the RAM23 region or the very C-terminal end of Notch. Notch then positively regulates a transcription factor encoded by tramtrack (ttk). This leads to Ttk expression in the daughter cell that does not inherit Numb. Thus, the inherited determinant Numb bestows a bias in the machinery for cell-cell communication to allow the specification of distinct daughter cell fates.

Animals↗
PubMed2003

Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis.

Numb and Numblike, conserved homologs of Drosophila Numb, have been implicated in cortical neurogenesis; however, analysis of their involvement in later stages of cortical development has been hampered by early lethality of double mutants in previous studies. Using Emx1(IREScre) to induce more restricted inactivation of Numb in the dorsal forebrain of numblike null mice beginning at E9.5, we have generated viable double mutants that displayed striking brain defects. It was thus possible to examine neurogenesis during the later peak phase (E12.5-E16.5). Loss of Numb and Numblike in dorsal forebrain resulted in neural progenitor hyperproliferation, delayed cell cycle exit, impaired neuronal differentiation, and concomitant defects in cortical morphogenesis. These findings reveal novel and essential function of Numb and Numblike during the peak period of cortical neurogenesis. Further, these double mutant mice provide an unprecedented viable animal model for severe brain malformations due to defects in neural progenitor cells.

Animals↗
PubMed1996

Mammalian NUMB is an evolutionarily conserved signaling adapter protein that specifies cell fate.

BACKGROUND: Drosophila numb was originally described as a mutation affecting binary divisions in the sensory organ precursor (SOP) lineage. The numb gene was subsequently shown to encode an asymmetrically localized protein which is required for binary cell-fate decisions during peripheral nervous system development. Part of the Drosophila NUMB protein exhibits homology to the SHC phosphotyrosine-binding (PTB) domain, suggesting a potential link to tyrosine-kinase signal transduction. RESULTS: A widely expressed mammalian homologue of Drosophila numb (dnumb) has been cloned from rat and is referred to here as mammalian Numb (mNumb). The mNUMB protein has a similar overall structure to dNUMB and 67 sequence similarity. Misexpression of mNumb in Drosophila during sensory nervous system precursor cell division causes identical cell fate transformations to those produced by ectopic dNUMB expression. In vitro, the mNUMB PTB domain binds phosphotyrosine-containing proteins, and SH3 domains of SRC-family tyrosine kinases bind to mNUMB presumably through interactions with proline-rich regions in the carboxyl terminus. Overexpression of full-length mNUMB in the multipotential neural crest stem cell line MONC-1 dramatically biases its differentiation towards neurons, whereas overexpression of the mNUMB PTB domain biases its differentiation away from neuronal fates. CONCLUSIONS: Our results demonstrate that mNUMB is an evolutionarily conserved functional homologue of dNUMB, and establish a link to tyrosine-kinase-mediated signal transduction pathways. Furthermore, our results suggest that mNUMB and dNUMB are new members of a family of signaling adapter molecules that mediate conserved cell-fate decisions during development.

Amino Acid Sequence↗
PubMed2003

Lethal giant larvae acts together with numb in notch inhibition and cell fate specification in the Drosophila adult sensory organ precursor lineage.

The tumor suppressor genes lethal giant larvae (lgl) and discs large (dlg) act together to maintain the apical basal polarity of epithelial cells in the Drosophila embryo. Neuroblasts that delaminate from the embryonic epithelium require lgl to promote formation of a basal Numb and Prospero crescent, which will be asymmetrically segregated to the basal daughter cell upon division to specify cell fate. Sensory organ precursors (SOPs) also segregate Numb asymmetrically at cell division. Numb functions to inhibit Notch signaling and to specify the fates of progenies of the SOP that constitute the cellular components of the adult sensory organ. We report here that, in contrast to the embryonic neuroblast, lgl is not required for asymmetric localization of Numb in the dividing SOP. Nevertheless, mosaic analysis reveals that lgl is required for cell fate specification within the SOP lineage; SOPs lacking Lgl fail to specify internal neurons and glia. Epistasis studies suggest that Lgl acts to inhibit Notch signaling by functioning downstream or in parallel with Numb. These findings uncover a previously unknown function of Lgl in the inhibition of Notch and reveal different modes of action by which Lgl can influence cell fate in the neuroblast and SOP lineages.

Animals↗
PubMed2000

Exploring the roles of emotional numbing, depression, and dissociation in PTSD.

Some researchers consider emotional numbing a cardinal feature of posttraumatic stress disorder (PTSD). Others view numbing symptoms as representing an overlap between PTSD, depression, and dissociation. In this study, we examined the ability of early emotional numbing, depression, and dissociation symptoms to predict PTSD. One-hundred sixty-one women who were recent victims of sexual or nonsexual assault were assessed prospectively for 12 weeks. Emotional numbing, depression, and dissociation were each associated with initial PTSD severity. Notably, regression analyses revealed that after depression and dissociation were accounted for, early numbing contributed to the prediction of later PTSD.

Adult↗
PubMed1998

Structure of a Numb PTB domain-peptide complex suggests a basis for diverse binding specificity.

The phosphotyrosine-binding (PTB) domain of Numb, a protein involved in asymmetric cell division, has recently been shown to bind to the adapter protein Lnx through an LDNPAY sequence, to the Numb-associated kinase (Nak) through a sequence that does not contain an NPXY motif and to GP(p)Y-containing peptides obtained from library screening. We show here that these diverse peptide sequences bind with comparable affinities to the Numb PTB domain at a common binding site on the surface of the protein. The NMR structure of the Numb PTB domain in complex with a GPpY-containing peptide reveals a novel mechanism of binding with the peptide in a helical turn that does not hydrogen bond to the PTB domain beta-sheet. These results suggest that PTB domains can potentially have multiple modes of peptide recognition and provide a structural basis from which the multiple functions of the Numb PTB domain during asymmetric cell division could arise.

Amino Acid Sequence↗
PubMed2003

CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth.

Axon growth during neural development is highly dependent on both cytoskeletal re-organization and polarized membrane trafficking. Previously, we demonstrated that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate and axon growth in cultured hippocampal neurons, possibly by interacting with tubulin heterodimers and promoting microtubule assembly. Here, we identify Numb as a CRMP-2-interacting protein. Numb has been shown to interact with alpha-adaptin and to be involved in endocytosis. We found that Numb was associated with L1, a neuronal cell adhesion molecule that is endocytosed and recycled at the growth cone, where CRMP-2 and Numb were colocalized. Furthermore, expression of dominant-negative CRMP-2 mutants or knockdown of CRMP-2 message with small-interfering (si) RNA inhibited endocytosis of L1 at axonal growth cones and suppressed axon growth. These results suggest that in addition to regulating microtubule assembly, CRMP-2 is involved in polarized Numb-mediated endocytosis of proteins such as L1.

Animals↗
PubMed2004

Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis.

Neural progenitor cells in the developing neocortex change over time to produce different neurons, a phenomenon that is also observed in other regions of the nervous system. Mouse Numb (also known as m-numb) and Numbl (also known as numblike or Nbl) are redundant but essential in maintaining virtually all progenitor cells during early neurogenesis. They do this by allowing cells to choose progenitor over neuronal fates. To determine whether their roles change as neurogenesis progresses, we conditionally ablated both genes in the embryonic dorsal forebrain after initial waves of neurogenesis. Here we report that these proteins continue to be required for progenitor-cell maintenance, contrary to recently reported findings. As occurs during early neurogenesis, the loss of Numb and Numbl causes premature progenitor-cell depletion and, consequently, a highly specific malformation of the neocortex and hippocampus. Because progenitor cells can proliferate without Numb and Numbl before neurogenesis, we propose that Numb-mediated asymmetric cell divisions, which diversify many cell fates in Drosophila melanogaster, represent a general mechanism in mammals for stem cells to balance self-renewal and differentiation.

Animals↗
PubMed2001

Impotence and genital numbness in cyclists.

Cyclists often complain of genital numbness and even of impotence. The purpose of this study was to determine if perineal compression during cycling causes changes in the penile blood supply, impotence and penile numbness. Forty healthy athletic men with a mean age of 30 +/- 5.3 years took part in the study. Transcutaneous penile oxygen pressure was obtained using a device consisting of a modified Clark pO2 electrode, attached to the glans of the penis. All men were measured in a standing position before, in a seated and standing position during and in a standing position after cycling. Additionally, a detailed interview was carried out with each man. The penile blood supply--which correlates with the transcutaneous PO2 at the glans-- decreased significantly in over 70% of the test subjects during cycling in a seated position. Cycling in a standing position did not show any alteration in the penile blood supply as compared to the values measured before exercising. Numbness of the genital region was reported by 61% of the cyclists. 19% of cyclists who had a weekly training distance of more than 400 km complained of erectile dysfunction. The results of the present study showed that there is a deficiency in penile perfusion due to perineal arterial compression. This could be a reason for penile numbness and impotence in long-distance cyclists. Therefore, we suggest restricting the training distance, and taking sufficient pauses during the course of prolonged and vigorous bicycle riding, in order to avoid penile numbness and impotence.

Adult↗
PubMed2000

Mouse numb is an essential gene involved in cortical neurogenesis.

During neurogenesis of the mammalian neocortex, neural progenitor cells divide to generate daughter cells that either become neurons or remain as progenitor cells. The mouse numb (m-numb) gene encodes a membrane-associated protein that is asymmetrically localized to the apical cell membrane of dividing cortical progenitor cells and may be segregated to only the apical daughter cell that has been suggested to remain as a progenitor cell. To examine m-numb function during neural development, we generated a loss-of-function mutant allele of m-numb. Mice homozygous for this mutation exhibit severe defects in cranial neural tube closure and precocious neuron production in the forebrain and die around embryonic day 11.5 (E11. 5). These findings suggest that m-numb is an essential gene that plays a role in promoting progenitor cell fate during cortical neurogenesis.

Animals↗
PubMed2004

A novel PTB-PDZ domain interaction mediates isoform-specific ubiquitylation of mammalian Numb.

LNX was originally cloned as a Numb PTB-binding molecule, and it was subsequently found to act as a RING finger-type E3 ubiquitin ligase for the ubiquitylation and degradation of mNumb. Numb is a PTB domain-containing protein that functions as an intrinsic determinant of cell fate in asymmetric cell division. In mammals, four protein isoforms arise from alternative mRNA splicing. Here we report that while all four protein isoforms bind to LNX, only p72 and p66 Numb isoforms are ubiquitylated and degraded. The p72 and p66 Numb proteins differ from the other two isoforms by the presence of an 11-amino acid sequence insert in the PTB domain (PTBi). We demonstrate that the isoform-specific ubiquitylation of mNumb is due to a novel interaction between the first PDZ domain (PDZ1) of LNX and the PTBi variant. Deletion of LNX PDZ1 domain resulted in loss of ubiquitylation and subsequent degradation of the PTBi form of Numb. Interestingly efficient PTBi ubiquitylation not only depends on association with the LNX PDZ1 domain but also requires binding to the canonical PTB-binding motif NPAY in LNX. Thus two distinct modes of PTBi-mediated interaction with LNX work in concert to allow the effective and specific degradation of the p72 and p66 isoforms of mNumb.

Amino Acid Substitution↗
PubMed2006

Hypnotically induced emotional numbing: the roles of hypnosis and hypnotizability.

This study investigated the roles of hypnotizability and hypnosis in suggested emotional numbing. Thirty-two high hypnotizable and 32 low hypnotizable participants were administered either a hypnotic or wake induction and were then presented with emotionally distressing and neutral images during a suggestion for emotional numbing or a control condition. Emotional response was indexed through self-report and EMG corrugator-muscle activity. High hypnotizable participants, in both the hypnosis and wake conditions, reported more diminished emotional responses on self-report and EMG corrugator-muscle activity than low hypnotizable participants during the emotional-numbing suggestion. These findings suggest that elevated hypnotic susceptibility, rather than hypnosis, is an important mediator of emotional numbing. The importance of individual differences in emotional numbing is discussed.

Adult↗
PubMed2005

Numb proteins specify asymmetric cell fates via an endocytosis- and proteasome-independent pathway.

Numb proteins are evolutionarily conserved signaling molecules that make the daughter cells different after asymmetric divisions by segregating to only one daughter. They contain distinct binding motifs for alpha-adaptin (alpha-Ada) and proteins with Eps15 homology (EH) domains, which regulate endocytosis, and for E3 ubiquitin ligases, which target proteins for proteasome-mediated degradation. In Drosophila melanogaster, Numb acts by inhibiting Notch activity to cause a bias in Notch-mediated cell-cell communication. These findings have led to the hypothesis that Numb modulates Notch signaling by using endocytosis and proteasomes to directly reduce Notch protein levels at the cell surface. Here we show that two Drosophila EH proteins, Eps15 homologue 1 (EH1) and the dynamin-associated 160-kDa protein (Dap160), negatively regulate Notch signaling. However, neither elimination of the binding motifs for endocytic proteins nor simultaneous reduction of proteasome activity affects the activity of Numb proteins. Our findings indicate that an endocytosis- and proteasome-independent pathway may mediate Numb signaling in asymmetric cell fate specification.

Amino Acid Motifs↗
PubMed2006

Numb chin syndrome--a reflection of systemic malignancy.

BACKGROUND: Numb chin is an uncommon underappreciated though well documented neurological manifestation of metastatic malignancy. CASE PRESENTATION: A 50-year-old patient presented with right numb chin for few days. No dental cause was found. He later developed generalized vague symptoms. In few weeks his liver and renal functions deteriorated. Blood picture showed leucoerythroblastic picture. CT scan and bone marrow biopsy done at this stage revealed underlying high grade lymphoblastic lymphoma. He went into multiorgan failure, requiring ventilatory support and death within a short period. CONCLUSION: Numb Chin is a syndrome which initially presents with unilateral numbness or orofacial pain in the distribution of the inferior alveolar nerve and its branches with an underlying systemic malignancy. We emphasise that physicians and dentists should consider metastatic cancer in any patient who presents with chin or jaw numbness where no other obvious cause for their complaint is found.

Journal Article↗
PubMed1995

Asymmetric localization of numb autonomously determines sibling neuron identity in the Drosophila CNS.

The central nervous system (CNS) represents an excellent model system for examining how a multitude of unique cell fates are specified. We find that asymmetric localization of the numb protein autonomously controls a binary cell fate decision in the Drosophila CNS. The simplest lineage in the Drosophila CNS is that of the MP2 precursor: it divides unequally to generate the dMP2 and vMP2 neurons. Both are interneurons but project in different directions: dMP2 projects its axon posteriorly while vMP2 projects anteriorly. During MP2 mitosis, numb is localized into dMP2 and excluded from vMP2. Loss of numb transforms dMP2 into vMP2, whereas ectopic numb produces the opposite transformation of vMP2 into dMP2. Thus, numb is asymmetrically localized in the dividing MP2 and is necessary and sufficient to autonomously specify dMP2 neuronal identity.

Animals↗
PubMed2006

Perioral numbness associated with intravenous pentamidine administration.

OBJECTIVE: To report a case of perioral numbness associated with intravenous pentamidine. CASE SUMMARY: A 56-year-old female with acute myelogenous leukemia in remission developed Pneumocystis carinii infection. Treatment was initiated with trimethoprim/sulfamethoxazole (TMP/SMX), but the patient subsequently developed a rash on day 10 of treatment. TMP/SMX was discontinued and intravenous pentamidine was started in order to complete a 21 day treatment course for P. carinii pneumonia (PCP). However, on day 3 of pentamidine treatment, the patient reported perioral numbness during the infusion. The numbness disappeared soon after completion of the infusion but recurred with all subsequent pentamidine infusions. DISCUSSION: Paresthesias in general and facial area numbness in particular have been reported with pentamidine administration. While it is possible such adverse events may be a result of pentamidine's effect on serum electrolytes and glucose, especially hypocalcemia and hypoglycemia, these laboratory values were not grossly affected by pentamidine in our patient. The Naranjo probability scale revealed a probable adverse reaction of perioral numbness associated with intravenous pentamidine. CONCLUSIONS: Pentamidine is considered an alternative agent to TMP/SMX in the treatment of PCP. Although they do not commonly occur, paresthesias have been reported with pentamidine therapy. Healthcare practitioners should be aware of this type of event in association with pentamidine administration, especially as it may not be associated with overt serum glucose or electrolyte disturbances.

Female↗
PubMed1995

[Syphilitic thoracic aortic aneurysm with destruction of vertebral body, producing numbness of lower extremities and paraplegia].

Numbness and paraplegia are uncommon complaints in patient with thoracic aortic aneurysm (TAA). The patient was a 64-year-old man. He suffered numbness and gait disturbance (paraplegia). The blood examination showed no positive findings except a Wassermann was positive. Roentgen examination of the chest showed two abnormal shadows like tumors. The CT and MRI revealed destruction of the vertebral bodies and TAAs adjacent to the spinal cord. After the graft replacement was performed, numbness and paraplegia disappeared. This suggests that in our patient the TAAs destruct the vertebral body and produce pressure on the spinal cord, causing numbness and paraplegia. We experienced a rare case of the syphilitic TAA producing bone destruction, numbness and paraplegia.

Aortic Aneurysm, Thoracic↗