Sonic hedgehog protein
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Location (UCSC) | Chr 7: 155.8 – 155.81 Mb | Chr 5: 28.66 – 28.67 Mb | |||||||
PubMed search | [3] | [4] |
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Sonic hedgehog protein (SHH) is encoded for by the SHH gene.[5] The protein is named after the video game character Sonic the Hedgehog.
This signaling molecule is key in regulating embryonic
Sonic hedgehog still plays a role in differentiation, proliferation, and maintenance of adult tissues. Abnormal activation of SHH signaling in adult tissues has been implicated in various types of
Discovery and naming
The hedgehog gene (
Two of these genes,
Function
Of the hh homologues, SHH has been found to have the most critical roles in development, acting as a
Sonic hedgehog has also been shown to act as an
).The SHH gene is a member of the hedgehog gene family with five variations of DNA sequence alterations or splice variants. Many systems and structures rely heavily on proper expression of the SHH gene and subsequent sonic hedgehog protein, earning it the distinction of being an essential gene to development.
Patterning of the central nervous system
The sonic hedgehog (SHH) signaling molecule assumes various roles in patterning the central nervous system (CNS) during vertebrate development. One of the most characterized functions of SHH is its role in the induction of the floor plate and diverse ventral cell types within the neural tube.[41] The notochord—a structure derived from the axial mesoderm—produces SHH, which travels extracellularly to the ventral region of the neural tube and instructs those cells to form the floor plate.[42] Another view of floor plate induction hypothesizes that some precursor cells located in the notochord are inserted into the neural plate before its formation, later giving rise to the floor plate.[43]
The neural tube itself is the initial groundwork of the vertebrate CNS, and the floor plate is a specialized structure, located at the ventral midpoint of the neural tube. Evidence supporting the notochord as the signaling center comes from studies in which a second notochord is implanted near a neural tube in vivo, leading to the formation of an ectopic floor plate within the neural tube.[44]
Sonic hedgehog is the
Although there is no direct evidence of a SHH
SHH is suggested to promote the activation function of Gli2 and inhibit repressive activity of Gli3. SHH also seems to promote the activation function of Gli3, but this activity is not strong enough.[59] The graded concentration of SHH gives rise to graded activity of Gli 2 and Gli3, which promote ventral and dorsal neuronal subtypes in the ventral spinal cord. Evidence from Gli3 and SHH/Gli3 mutants show that SHH primarily regulates the spatial restriction of progenitor domains rather than being inductive, as SHH/Gli3 mutants show intermixing of cell types.[59][61]
SHH also induces other proteins with which it interacts, and these interactions can influence the sensitivity of a cell towards SHH. Hedgehog-interacting protein (HHIP) is induced by SHH, which in turn attenuates its signaling activity.[62] Vitronectin is another protein that is induced by SHH; it acts as an obligate co-factor for SHH signaling in the neural tube.[63]
There are five distinct progenitor domains in the ventral neural tube:
It is important to note that SHH is not the only
Morphogenetic activity
The concentration- and time-dependent, cell-fate-determining activity of SHH in the
It is thought that the SHH gradient works to elicit multiple different cell fates by a concentration- and time-dependent mechanism that induces a variety of transcription factors in the ventral
The spatial and temporal aspect of the progressive induction of genes and cell fates in the ventral neural tube is illustrated by the expression domains of two of the most well-characterized transcription factors, Olig2 and Nkx2.2.[68] Early in development, the cells at the ventral midline have only been exposed to a low concentration of SHH for a relatively short time and express the transcription factor Olig2.[68] The expression of Olig2 rapidly expands in a dorsal direction concomitantly with the continuous dorsal extension of the SHH gradient over time.[68] However, as the morphogenetic front of SHH ligand moves and begins to grow more concentrated, cells that are exposed to higher levels of the ligand respond by switching off Olig2 and turning on Nkx2.2,[68] creating a sharp boundary between the cells expressing the transcription factor Nkx2.2 ventral to the cells expressing Olig2. It is in this way that each of the domains of the six progenitor cell populations are thought to be successively patterned throughout the neural tube by the SHH concentration gradient.[68] Mutual inhibition between pairs of transcription factors expressed in neighboring domains contributes to the development of sharp boundaries; however, in some cases, inhibitory relationship has been found even between pairs of transcription factors from more distant domains. Particularly, NKX2-2 expressed in the V3 domain is reported to inhibit IRX3 expressed in V2 and more dorsal domains, although V3 and V2 are separated by a further domain termed MN.[71]
SHH expression in the frontonasal ectodermal zone (FEZ), which is a signaling center that is responsible for the patterned development of the upper jaw, regulates craniofacial development mediating through the miR-199 family in the FEZ. Specifically, SHH-dependent signals from the brain regulate genes of the miR-199 family with downregulations of the miR-199 genes increasing SHH expression and resulting in wider faces, while upregulations of the miR-199 genes decrease SHH expression resulting in narrow faces.[72]
Tooth development
SHH plays an important role in organogenesis and, most importantly, craniofacial development. Being that SHH is a signaling molecule, it primarily works by diffusion along a concentration gradient, affecting cells in different manners. In early tooth development, SHH is released from the primary enamel knot—a signaling center—to provide positional information in both a lateral and planar signaling pattern in tooth development and regulation of tooth cusp growth.[73] SHH in particular is needed for growth of epithelial cervical loops, where the outer and inner epitheliums join and form a reservoir for dental stem cells. After the primary enamel knots are apoptosed, the secondary enamel knots are formed. The secondary enamel knots secrete SHH in combination with other signaling molecules to thicken the oral ectoderm and begin patterning the complex shapes of the crown of a tooth during differentiation and mineralization.[74] In a knockout gene model, absence of SHH is indicative of holoprosencephaly. However, SHH activates downstream molecules of Gli2 and Gli3. Mutant Gli2 and Gli3 embryos have abnormal development of incisors that are arrested in early tooth development as well as small molars.[75]
Lung development
Although SHH is most commonly associated with brain and limb digit development, it is also important in lung development.[76][77][78][79] Studies using qPCR and knockouts have demonstrated that SHH contributes to embryonic lung development. The mammalian lung branching occurs in the epithelium of the developing bronchi and lungs.[80][81] SHH expressed throughout the foregut endoderm (innermost of three germ layers) in the distal epithelium, where the embryonic lungs are developing.[78][81] This suggests that SHH is partially responsible for the branching of the lungs. Further evidence of SHH's role in lung branching has been seen with qPCR. SHH expression occurs in the developing lungs around embryonic day 11 and is strongly expressed in the buds of the fetal lungs but low in the developing bronchi.[78][81] Mice who are deficient in SHH can develop tracheoesophageal fistula (abnormal connection of the esophagus and trachea).[82][78] Additionally, a double (SHH-/- ) knockout mouse model exhibited poor lung development. The lungs of the SHH double knockout failed to undergo lobation and branching (i.e., the abnormal lungs only developed one branch, compared to an extensively branched phenotype of the wildtype).[78]
Potential regenerative function
Sonic hedgehog may play a role in mammalian hair cell regeneration. By modulating retinoblastoma protein activity in rat cochlea, sonic hedgehog allows mature hair cells that normally cannot return to a proliferative state to divide and differentiate. Retinoblastoma proteins suppress cell growth by preventing cells from returning to the cell cycle, thereby preventing proliferation. Inhibiting the activity of Rb seems to allow cells to divide. Therefore, sonic hedgehog—identified as an important regulator of Rb—may also prove to be an important feature in regrowing hair cells after damage.[83]
SHH is important for regulating dermal adipogenesis by hair follicle transit-amplifying cells (HF-TACs). Specifically, SHH induces dermal angiogenesis by acting directly on adipocyte precursors and promoting their proliferation through their expression of the peroxisome proliferator-activated receptor γ (Pparg) gene.[84]
Processing
SHH undergoes a series of processing steps before it is secreted from the cell. Newly synthesised SHH weighs 45
Robotnikinin
A potential inhibitor of the Hedgehog signaling pathway has been found and dubbed "Robotnikinin"—after Sonic the Hedgehog's nemesis and the main antagonist of the Sonic the Hedgehog game series, Dr. Ivo "Eggman" Robotnik.[89]
Former controversy surrounding name
The gene has been linked to a condition known as holoprosencephaly, which can result in severe brain, skull and facial defects, causing a few clinicians and scientists to criticize the name on the grounds that it sounds too frivolous. It has been noted that mention of a mutation in a sonic hedgehog gene might not be well received in a discussion of a serious disorder with a patient or their family.[17][90][91] This controversy has largely died down, and the name is now generally seen as a humorous relic of the time before the rise of fast, cheap complete genome sequencing and standardized nomenclature.[92] The problem of the "inappropriateness" of the names of genes such as "Mothers against decapentaplegic," "Lunatic fringe," and "Sonic hedgehog" is largely avoided by using standardized abbreviations when speaking with patients and their families.[93]
Gallery
See also
- Pikachurin, a retinal protein named after Pikachu
- Zbtb7, an oncogene which was originally named "Pokémon"
References
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Further reading
- Dorus S, Anderson JR, Vallender EJ, Gilbert SL, Zhang L, Chemnick LG, et al. (July 2006). "Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates". Human Molecular Genetics. 15 (13): 2031–2037. PMID 16687440.
- Gilbert SF (2000). Developmental biology (6th ed.). Sunderland, Mass: Sinauer Associates. ISBN 978-0-87893-243-6.
- Kim J, Kim P, Hui CC (May 2001). "The VACTERL association: lessons from the Sonic hedgehog pathway". Clinical Genetics. 59 (5): 306–315. S2CID 34304310.
- Morton JP, Lewis BC (July 2007). "Shh signaling and pancreatic cancer: implications for therapy?". Cell Cycle. 6 (13): 1553–1557. S2CID 4670615.
- Mullor JL, Sánchez P, Ruiz i Altaba A (December 2002). "Pathways and consequences: Hedgehog signaling in human disease". Trends in Cell Biology. 12 (12): 562–569. PMID 12495844.
- Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M (July 2001). "SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature". American Journal of Medical Genetics. 102 (1): 1–10. PMID 11471164.
- Williams JA (December 2005). "Hedgehog and spinal cord injury". Expert Opinion on Therapeutic Targets. 9 (6): 1137–1145. S2CID 5548531.
External links
- An introductory article on SHH at Davidson College
- Rediscovering biology: Unit 7 Genetics of development .. Expert interview transcripts interview with John Incardona PhD .. explanation of the discovery and naming of the sonic hedgehog gene
- ‘Sonic Hedgehog’ sounded funny at first .. New York Times November 12, 2006 ..
- GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
- SHH – sonic hedgehog US National Library of Medicine
- Overview of all the structural information available in the PDB for UniProt: Q15465 (Human Sonic hedgehog protein) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: Q62226 (Mouse Sonic hedgehog protein) at the PDBe-KB.