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Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
The limb bud expresses the transcription factors homeobox protein aristaless-like 4 (Alx4) in the anterior region and homeobox protein b8 (Hoxb8) in the posterior region (Figure 2.10). The zone of polarizing activity (ZPA), which determines the anterior-posterior axis of the developing limb, arises where Hoxb8’s expression intersects the AER (Charite et al. 1994). The ZPA is marked by the expression of Shh, BMP2, BMP4, and FGF4. FGF4 and BMP2 regulate the proliferation of the underlying mesenchyme with counteracting roles; FGF4 stimulates proliferation, while BMP2 inhibits proliferation and initiates chondrogenesis (Niswander and Martin 1993a,b; Niswander et al. 1994). The AER produces a feedback loop of FGF8 (initiated by Wnt3a and interacting with FGF10) and FGF4 (which regulates Shh) (Moon and Capecchi 2000). Shh signaling helps maintain FGF10 secretion, which induces proliferation in the mesoderm; it also upregulates the BMP antagonist Gremlin in the mesenchyme, inhibiting BMP and maintaining proliferation (Zuniga et al. 1999). Maintenance of the FGF10 expression is also under control by two different Wnt family members (Wnt2b and Wnt8c). Experimental work in chick limb buds has demonstrated that the function of the AER can be duplicated by the implantation of an FGF4 bead at the site where the AER was removed (Niswander et al. 1994). This is sufficient to upregulate Msx1 expression, which is then maintained by FGF2 and BMP4 (Tickle 2002, 2003). DLX5 (distal-less homeobox) transcription factor is also transiently expressed with implantation of FGF2-soaked beads, and chick limb studies indicate DLX5 may be needed to maintain the AER (Ferrari et al. 1999). The DLX family has been implicated in the regulation of craniofacial cartilages in zebrafish models (Ellies et al. 1997). DLX5 is expressed in hypertrophic chondrocytes and areas of chondrocytes initiating differentiation, and appears to be under the control of BMP7 (Holleville et al. 2003). It should be noted that while a somewhat linear process is described above, the precise hierarchical relationship and cross-regulation of these factors by Hox genes are still unclear.
Human-leukocyte antigen class II genes in early-onset obsessive-compulsive disorder
Published in The World Journal of Biological Psychiatry, 2019
Natalia Rodriguez, Astrid Morer, E. Azucena González-Navarro, Patricia Gassó, Daniel Boloc, Carles Serra-Pagès, Amalia Lafuente, Luisa Lazaro, Sergi Mas
In the central nervous system, expression of MHC class II genes has traditionally been restricted to microglial cells. However, a recent study identified a subpopulation of human neural stem cells which express MHC class II molecules during development (Vagaska et al. 2016). Given the proposed crosstalk between neurons and microglia in the normal brain, transient MHC-II expression in embryonic neurons may play a role in microglial development (Eyo & Wu 2013). A specific role for microglia in the pathophysiology of OCD has been suggested by a recent mouse model of OCD symptomatology (Greer & Capecchi 2002). Mice with disruptions of the HoxB8 gene, a homeobox developmental patterning gene expressed prominently in macrophage-lineage haematopoietic cells, were observed to exhibit excessive grooming behaviour. More recently, mutations in the Hoxb8 gene in the microglia have been found to be necessary and sufficient for developing this phenotype. Transplantation of wild-type bone marrow into mutant Hoxb8 mice reversed this phenotype by allowing repopulation of the brain with wild-type microglia. Conversely, transplant of Hoxb8 mutant bone marrow into wild-type mice can induce pathological grooming behaviour (Chen et al. 2010). The mechanisms of this effect remain unclear. In the brain, a subset of microglia (although not all) express Hoxb8. The specific physiological role of this particular subset of Hoxb8 + microglia has yet to be described. The few post-mortem studies in OCD performed to date have not investigated microglial activation.