Of the
hh homologues,
SHH has been found to have the most critical roles in development, acting as a
morphogen involved in patterning many systems—including the
anterior pituitary,
pallium of the brain,
spinal cord,
lungs, teeth and the
thalamus by the
zona limitans intrathalamica. In vertebrates, the
development of
limbs and
digits depends on the secretion of sonic hedgehog by the
zone of polarizing activity, located on the posterior side of the embryonic
limb bud. and
medulloblastoma, as well as the progression of
prostate cancer tumours. For SHH to be expressed in the developing embryo limbs, a morphogen called
fibroblast growth factors must be secreted from the
apical ectodermal ridge. Sonic hedgehog has also been shown to act as an
axonal guidance cue. It has been demonstrated that SHH attracts
commissural axons at the ventral midline of the developing spinal cord. Specifically, SHH attracts
retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations. The absence (non-expression) of SHH has been shown to control the growth of nascent hind limbs in
cetaceans (
whales and
dolphins). The
SHH gene is a member of the hedgehog gene family with five variations of DNA sequence alterations or splice variants.
SHH is located on chromosome seven and initiates the production of Sonic Hedgehog protein. If the
SHH gene is mutated or absent, the protein Sonic Hedgehog cannot do its job properly. Sonic hedgehog contributes to cell growth, cell specification and formation, structuring and organization of the body plan. This protein functions as a vital morphogenic signaling molecule and plays an important role in the formation of many different structures in developing embryos. and facial dysmorphia.
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. 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. 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. 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. Sonic hedgehog is the
secreted protein that mediates signaling activities of the notochord and floor plate. Studies involving
ectopic expression of SHH
in vitro and
in vivo result in floor plate induction and
differentiation of
motor neuron and ventral
interneurons. On the other hand, mice mutants for SHH lack ventral spinal cord characteristics.
In vitro blocking of SHH signaling using
antibodies against it shows similar phenotypes. so that a high concentration of SHH results in a local
inhibition of
cellular proliferation. This inhibition causes the floor plate to become thin compared to the lateral regions of the
neural tube. Lower concentration of SHH results in cellular proliferation and induction of various ventral neural cell types. throughout the ventral neural tube.
In vitro studies show that incremental two- and threefold changes in SHH concentration give rise to motor neuron and different interneuronal subtypes as found in the ventral spinal cord. These incremental changes
in vitro correspond to the distance of
domains from the signaling tissue (notochord and floor plate) which subsequently differentiates into different neuronal subtypes as it occurs
in vitro. Graded SHH signaling is suggested to be mediated through the
Gli family of proteins, which are vertebrate homologues of the
Drosophila zinc-finger-containing
transcription factor Cubitus interruptus (
Ci).
Ci is a crucial mediator of hedgehog (
Hh) signaling in
Drosophila. In vertebrates, three different Gli proteins are present, viz.
Gli1,
Gli2 and
Gli3, which are expressed in the neural tube. Mice mutants for Gli1 show normal spinal cord development, suggesting that it is dispensable for mediating SHH activity. However, Gli2 mutant mice show abnormalities in the ventral spinal cord, with severe defects in the floor plate and ventral-most interneurons (V3). Gli3
antagonizes SHH function in a
dose-dependent manner, promoting dorsal neuronal subtypes. SHH mutant phenotypes can be rescued in a SHH/Gli3 double
mutant. Gli proteins have a C-terminal activation domain and an N-terminal repressive domain. 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. 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.
Vitronectin is another protein that is induced by SHH; it acts as an obligate co-factor for SHH signaling in the neural tube. There are five distinct progenitor domains in the ventral neural tube:
V3 interneurons, motor neurons (MN),
V2,
V1, and V0 interneurons (in ventral to dorsal order). It is important to note that SHH is not the only
signaling molecule exerting an effect on the developing neural tube. Many other molecules,
pathways and mechanisms are active (e.g.,
RA,
FGF,
BMP), and complex interactions between SHH and other molecules are possible. BMPs are suggested to play a critical role in determining the sensitivity of neural cell to SHH signaling. Evidence supporting this comes from studies using BMP inhibitors that ventralize the fate of the neural plate cell for a given SHH concentration. On the other hand, mutation in BMP antagonists (e.g.,
noggin) produces severe defects in the ventral-most characteristics of the spinal cord, followed by
ectopic expression of BMP in the ventral neural tube. Interactions of SHH with Fgf and RA have not yet been studied in molecular detail.
Morphogenetic activity The concentration- and time-dependent, cell-fate-determining activity of SHH in the
ventral neural tube makes it a prime example of a
morphogen. In vertebrates, SHH signaling in the ventral portion of the neural tube is most notably responsible for the induction of
floor plate cells and
motor neurons. SHH emanates from the
notochord and ventral floor plate of the developing neural tube to create a
concentration gradient that spans the dorso-ventral axis and is antagonized by an inverse
Wnt gradient, which specifies the dorsal spinal cord. Higher concentrations of the SHH ligand are found in the most ventral aspects of the neural tube and notochord, while lower concentrations are found in the more dorsal regions of the neural tube. 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
progenitor cells. 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.
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. 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. 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.
Lung development Although SHH is most commonly associated with brain and limb digit development, it is also important in lung development. 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. SHH expressed throughout the foregut
endoderm (innermost of three germ layers) in the distal epithelium, where the embryonic lungs are developing. 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.
Clinical Significance Recent studies have shown that abnormalities in SHH signaling pathways are associated with both neurodegenerative diseases and developmental disorders. Mutations in the SHH gene can result in conditions such as holoprosencephaly, a brain defect caused by failure of the embryonic forebrain to divide into two hemispheres. In addition to its role in development, SHH has been linked to diseases that affect the adult nervous system. In Alzheimer’s disease, SHH signaling is altered and may be involved in neuronal damage and cognitive impairment. Studies suggest that it can have both protective and harmful roles depending on the biological conditions. SHH is shown to have a protective role in Parkinson’s disease by supporting the survival of dopaminergic neurons and reducing oxidative stress. Experimental studies show that increasing SHH signaling can improve motor function in animal models with Parkinson’s disease. Knockout studies have shown that a loss of SHH function can lead to severe developmental abnormalities, including brain and spinal cord defects, missing limb structures and malformations in midline structures such as the notochord. Overall, SHH signaling plays different roles in embryonic development, where it is essential for organogenesis, compared to adults, where changes in its pathway can positively influence neuronal survival or, when dysregulated, can contribute to cognitive impairment and behavioral changes. == Processing ==