JAM-B 세포

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비대칭적 수상돌기장을 보여주는 JAM-B 세포의 측면 그림.Cite error: Invalid <ref> tag; refs with no content must have a name

J 망막 신경절 세포(J-RGC)라고도 하는 JAM-B 세포는 생쥐에서 처음 발견된 On-OFF 방향 선택적 신경절 세포의, 분자생물학적으로 정의된, 한 종류 입니다. JAM-B 세포의 발견은 망막에 있는 서로 다른 종류의 세포들을 정의하고 분류하는 데 매우 중요했는데 그 이유는 분자 표지자의 존재에 기반해 분류가 된 최초의 세포이기 때문입니다. 이 세포의 이름을 붙여주고 이들 세포를 망막 신경절 세포 중 특정하게 구분되는 하나의 군으로 만들어준 생체지표는 Junctional Adhesion Molecule B라고 불리는 단백질입니다(JAM-B).

JAM-B 세포들은 JAM-B 분자 생체지표의 존재 이외에 많은 기능적, 구조적인 특징들을 공유합니다. 예를 들면, 대부분의 J-망막 신경절 세포들은 등쪽에서 배쪽 방향으로 망막을 가로지르며 정렬된 비대칭적 수지상 가지를 가지고 있습니다. 현저하게 비대칭적인 수지상 가지를 보유하는 이들 J-망막 신경절 세포들은 또한 비대칭적인 수용장을 가지고 있습니다. 추가적으로 J-망막 신경절 세포들은 방향 선택적이고 특별히 위쪽을 향하는 움직임에 반응합니다. 더욱이 이들 세포들은 모두 OFF 망막 신경절 세포들로, 움직이는 밝은 자극의 앞서 이끄는 가장자리 보다는, 수용장 중심의 빛 감소 또는 끌리는 꼬리의 가장자리에 반응을 합니다.[1]

해부학적 구조(Anatomy)

형태

J-망막 신경절 세포 수상돌기의 방향(화살표)을 보여주는 망막 스케치. 파란 별들은 등쪽 및 배쪽 가장자리에 있는 대칭적 수상돌기를 가진 세포를 나타냅니다. 흰 별은 시신경 머리입니다. D, 등쪽 dorsal; V, 배쪽 ventral; N,코쪽 nasal; T, 측두쪽 temporal. 막대자길이, 50 mm.Cite error: Invalid <ref> tag; refs with no content must have a name

약 85%의 JAM-B 세포에서, 수지상 가지에서 현저한 비대칭성이 존재합니다. 이들 경우에, 수지상 가지의 90 퍼센트 이상이 세포체 쪽에 존재합니다. 수지상 가지의 비대칭은 망막 신경절 세포에 있어서는 일반적이지 않은 현상인데 왜냐하면 대부분의 망막 신경절 세포 수상돌기는 대칭적이기 때문입니다. 따라서 많은 비율의 JAM-B 세포에서 이러한 비대칭이 우세하게 나타난다는 사실은 주목할 만 합니다. 더 주목할 만한 것은 JAM-B 세포의 비대칭적 수상돌기가 모두 같은 방향(배쪽에서 코쪽으로 약 13도)을 향한다는 것입니다. 시신경 머리에 대해 방사형이라기 보다는 종적인(등쪽에서 배쪽으로) 수상돌기 오리엔테이션이 존재합니다.Cite error: Invalid <ref> tag; refs with no content must have a name

반면, 약15% 의JAM-B 세포들은 그렇게 비대칭적이지 않습니다. 이들 비대칭적이지 않은 JAM-B 세포들은 거의 모두가 망막의 등쪽 및 배쪽 가장자리에 위치하고 있습니다. 따라서 망막의 코쪽, 중심 및 측두 구역에 있는 거의 모든 JAM-B 세포는 현저하게 비대칭적입니다.Cite error: Invalid <ref> tag; refs with no content must have a name

연결(Connections)

BD-, W3- 및 W7 망막 신경절 세포의 층제한에 비해 J-망막 신경절 세포의 수상돌기 뻩음이 내망상층(외촉 상단 상자)의 바깥 1/3에 층제한 되어 있는 것을 볼 수 있습니다.[2]

JAM-B 세포의 수상돌기들은 도파민성 및 콜린성 무축삭 세포의 돌기들 사이에 있는 좁은 띠 에 가지를 형성하는 것으로 알려져있습니다. 실제로, 대칭성 및 비대칭성 JAM-B 들 수상돌기들은 모두 내망상층의 바깥쪽 1/3 부분에 국한되어 있습니다.

내망상층의 바깥쪽 절반 부분에 가지를 뻗은 수상돌기를 가지고 있는 망막 신경절 세포들은 일반 적으로 OFF-망막 신경절 세포- 예, 수용장 중심의 빛 감소에 반응-라고 합니다[3] 주의할 것은, ON 양극성 세포의 돌기들은 J-망막 신경절 세포와 최소만 겹치는 데 반해서, 다수의 OFF 양극성 세포 종류들이 J-망막 신경절 세포의 수상돌기와 같은 아층판에 돌기들을 가지고 있다는 것입니다. 따라서 J-망막 신경절 세포의 가지 뻗은 양상으로 인해 Kim과 동료들이 이들 세포가 OFF 망막 신경절 세포라는 가설을 처음 세울 수 있게 해주었습니다.[3] Notably, several subcategories of OFF bipolar cell have processes in the same sublaminae as J-RGC dendrites, while processes of ON bipolar cells have been found to overlap minimally with J-RGCs. Thus the arborization pattern of J-RGCs led Kim et al. to first hypothesize that these cells are OFF retinal ganglion cells.Cite error: Invalid <ref> tag; refs with no content must have a name

J-망막 신경절 세포의 수상돌기는 내망상층의 바깥쪽 1/3 부분에 도달하기 전에 내망상층의 중간 부분에 수차례 가지를 뻗습니다. 가지를 더 뻗고 가지의 말단이 존재하는 부분은 내망상층의 바깥쪽 1/3 부분입니다. 비대칭적 및 대칭적 군들의 수상돌기들은 모두 내망상층의 중간 부위에서 몇 차례 가지를 뻗고, 그 다음으로 바깥쪽 가장자리로 올라가며 거기서 추가적으로 가지를 뻗으며 가지의 말단이 아층판 2(그림 참조)에 위치하게 됩니다.Cite error: Invalid <ref> tag; refs with no content must have a name

Kim 과 동료들은 생쥐에서 두뇌로 가는 JAM-B 세포의 돌기를 추적하기 위해서 노란색 형광 단백질을 사용했습니다. 그들은 JAM-B 세포가 상구(superior colliculus)에 많이 뻗고 있다는 것을 밝혔습니다. 따라서 생쥐에선 상방 움직임의 감지에 대해 집중적인 투자가 있었던 것 같습니다. 이게 왜 그런지는 정확히 밝혀져야 할 것입니다.Cite error: Invalid <ref> tag; refs with no content must have a name

Physiology

Kim et al. found that J-RGCs exhibited three notable physiological asymmetries. These asymmetries, in order of their discussion here, are the direction of displacement of receptive field surround (and related asymmetric light response), the preferred direction for movement of a spot of light, and the space-time slant within the receptive field center.[4]

Light Response and its Correlation to Dendrite Orientation

JAM-B cells are OFF retinal ganglion cells, meaning that they respond to a decrease in light levels. Kim et al. probed J-RGCs with flashing lights and found that almost all fired when the light turned off. On the other hand, RGCs lacking evidence of JAM-B were nearly equally likely to be ON or OFF cells.

Furthermore, the receptive field of J-RGCs is unusual in that the integrated strength of its ON surround exceeds that of the OFF centre. Kim et al. reached this conclusion after recording the response of J-RGCs to different sizes of flashing light spots centered at the soma (cell body). When the flashing spot was of a certain large enough size, the J-RGC sometimes failed to respond. Upon increasing the size of flashing spot even further, Kim et al. found that the J-RGCs tended to respond at light onset. Thus the strength of the JAM-B cells' ON surround exceeds that of their OFF center--an unusual feature in a retinal ganglion cell.

Studies imply that no sizable populations of OFF RGCs exist with asymmetric dendrites pointing in directions other than dorsal-to-ventral.[5]

Upward Motion Selectivity

JAM-B cells respond selectively to upward motion. To test the direction sensitivity of each sample J-RGC, Kim et al. moved a small spot through its receptive field center along eight straight-line trajectories of different orientation. They found that the response correlated strongly with the direction of the spot's motion. Furthermore, the direction eliciting the most response matched the general direction in which the asymmetric dendritic tree pointed away from the J-RGC soma. In contrast, it had previously been found that direction-selective ganglion cells generally lack a correlation between physiological sensitivity and structural asymmetry.[4]

Kim et al. proposed that the asymmetry of a JAM-B cell's dendritic arbors is related to this direction selectivity, stating, "across the entire J-RGC population, the degree of direction selectivity was correlated with the degree of asymmetry of the receptive field. It has been found in another study that when probed with a small moving spot, the firing rate of J-RGCs correlated strongly with the direction of motion. The preferred direction of motion corresponds to the direction of the dendritic arbor from the soma"[5] As Kim et al. claim, "within a single molecularly defined class of OFF-RGCs, dendritic structure and cell function are closely linked, suggesting that the latter arises from the former." [4]

Whereas the selectivity of other direction-selective RGCs depends on input from starburst amacrine cells, which themselves show directional responses, J-RGCs receive little input from these cells and thus must rely on other mechanisms. One possible mechanism is suggested by the finding that inhibitory synapses on some RGCs are concentrated at distal dendrites. Distal inhibition on the asymmetric dendrites of J-RGCs could account for their asymmetrically displaced surround.[4]

Features of the JAM-B Receptive Field Shaping Direction Selectivity

Diagram showing the spatio-temporal receptive field of a J-RGC, computed based on a J-RGC's responses to a strip of narrow bars centered on the cell, with each bar jittering randomly and independently of the other bars.[4]

The ON surround of a JAM-B cell is typically asymmetric, in that it is shifted in the direction of preferred motion relative to the center. The receptive field center was found by Kim et al. to possess an OFF portion with an additional ON "overshoot." This ON feature of the center combines functionally with the ON surround such that a light moving in the preferred direction across the receptive field will pass through the combined ON features of center and surround. If the light is moving at the right speed, the time delay of the center invokes a superposition of the excitation of the ON and OFF regions, thus eliciting an enhanced response (see figure). It is this mechanism which purportedly allows an OFF RGC to respond to bright lights with strong direction-selectivity.

Furthermore, Kim et al. found that the OFF center is biased in the space-time plane such that it is longer in the direction of preferred motion. This slanting of the OFF center renders the region more responsive to objects moving in the preferred direction (as opposed to objects moving perpendicular to the preferred direction.

An additional finding of Kim et al. is that the space-time slope of the OFF center is significantly greater than that of the ON-surround. As a result, a dark spot elicits a response of higher magnitude from the J-RGC when moving quickly, while a light spots elicits the greatest response at low speeds[4]

Molecules

JAM-B Cells are classified by the expression of the Junctional adhesion molecule B (JAM-B) protein.

Junctional adhesion molecule B is a protein that in humans is encoded by the JAM2 gene. JAM2 has also been designated as CD322 (cluster of differentiation 322). Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is localized in the tight junctions between high endothelial cells. It acts as an adhesive ligand for interacting with a variety of immune cell types and may play a role in lymphocyte homing to secondary lymphoid organs [6].

Development

The pattern by which retinal ganglion cells develop in the retina varies by subtype. It has been found that J-RGCs develop via a gradual restriction of a diffuse pattern. The dendrites of J-RGC cells have been found to extend throughout the entire inner plexiform layer at P5 in mice. At P8 in mice it was found that branches had been pruned in the inner portion of the inner plexiform layer, while in the outer portion of the Inner Plexiform Layer the branches had propagated. In fact, they were found to have their arbors centered around starburst amacrines in SL3. Gradually the arbor distributions were found to shift outward through the IPL until P12, when they had achieved their adult pattern of restriction to LS2.[5]

History

JAM-B cells were first discovered by In-Jung Kim, Yifeng Zhang, Masahito Yamagata, Markus Meister, and Joshua R. Sanes of Harvard's Department of Molecular and Cellular Biology and Center for Brain Science.

To mark JAM-B cells for structural and functional study, they generated mice that expressed a ligand–activated Cre recombinase oestrogen receptor fusion protein 10 (CreER) under the control of regulatory elements from the JAM-B gene.

Before the discovery of JAM-B cells, retinal ganglion cells lacked a labeling system based on molecular markers. Thus Retinal Ganglion Cells were categorized by nonselective factors or else treated as a single population. Thus RGCs were often either subject to subjective classification or inaccurate overgeneralization.[4] Today, RGC subtypes in addition to JAM-B cells have been classified based on reporter genes. These subtypes include BD-, W3-, and W7-RGCs. These subsets can be identified using transgenic lines to mark them.

Transgenic lines that mark RGC subsets. Scale bar: (in g ) b–g , 100 μm.[5]

Open Questions/Status

Relationship between J-RGCs and direction-selective collicular cells

The collicular termination of J-RGCs (of which JAM-B cells are a majority) is intriguing in light of a study in which Drager and Hubel mapped the receptive fields of neurons in the superior colliculus of the mouse. Nearly all of the direction-selective neurons they studied (35 out of 38) preferred upward motion in the visual field. This preference corresponds to that of J-RGCs.[4] Kim et al. have proposed that the receptive fields of direction-selective collicular cells are built from J-RGCs. Research remains to be done on this topic.

Sensitivity to upward motion in mice

It is uncertain why the mouse seems to have invested so heavily in sensitivity to upward motion. Kim et al. have suggested mating JAM-B–CreER mice to other transgenics bearing appropriate Cre-activated channels or toxins. Thus it could be possible to inactivate the pathway and thereby directly test its function.[4]

References

  1. In-Jung Kim et al. Molecular identification of a retinal cell type that responds to upward motion (2008). Nature 452: 478-482
  2. In-Jung Kim et al. Laminar Restriction of Retinal Ganglion Cell Dendrites and Axons: Subtype-Specific Developmental Patterns Revealed with Transgenic Markers (2010). The Journal of Neuroscience. 30 (4): 1452-1462
  3. Wässle, H. Parallel processing in the mammalian retina (2004). Nat Rev Neuroscience. 5: 747-757
  4. Cite error: Invalid <ref> tag; no text was provided for refs named kim2008
  5. Cite error: Invalid <ref> tag; no text was provided for refs named kim2010
  6. JAM2