Question

1. Noncanonical Ca2+ wnt signaling results in release of Ca2+ from intracellular stores. If a mutation causes constitutive activation of the pathway in a muscle cell what would the consequence be?
2. Mutations in the S3 site of Notch makes it impossible for g-secretin to cleave notch. Given that Notch signaling is important for lateral inhibition, how would such a mutation affect differentiation of a local cluster of stem cells?

Answer 1

A) Noncanonical Ca2+ Wnt signaling results in release of Ca2+ from intracellular stores. If a mutation causes constitutive activation of the pathway in a muscle cell what would the consequence be?

The Wnt signaling pathway is activated by Wnt-proteins binding to the receptor. The noncanonical Wnt calcium pathway regulates the levels of calcium in cells by controlling the section of calcium from the intracellular claim stores such as the endoplasmic reticulum (ER).

In a muscle cell, the release of calcium is a primary signal that leads to the contraction of the muscle. Constitutive activation of the pathway would lead to a continuous influx of calcium from the ER, causing a sustained contraction of the muscle cell.

Under normal conditions, in response to the elevated levels of calcium, there is an activation of pumps such as the SR/ER calcium ATPase pump (SERCA) which is responsible for pumping back the calcium to the ER, at the expense of ATP. Although the SERCA pump would pump the excessive calcium back to ER, the excessive pumping caused due to the consecutive activation of the noncanonical calcium Wnt pathway will lead to a state of hypermetabolism. This will eventually cause substantially lower levels of ATP, acidosis, tachycardia (rapid heart beating), and hyperthermia. These events are also collectively termed as malignant hyperthermia in the case of skeletal muscles.

B) Mutations in the S3 site of Notch makes it impossible for g-secretin to cleave notch. Given that Notch signaling is important for lateral inhibition, how would such a mutation affect differentiation of a local cluster of stem cells?

Notch pathway is a common pathway in animal cells that plays a role in communicating transcriptional signals. It plays a crucial role in processes such as stem cell differentiation and maturation.

Notch pathway consists of notch receptor, notch ligands (for example 'delta'), and proteins that transmit the signal from notch to nucleus, leading to an alteration of gene expression. The notch receptor is composed of extracellular and intracellular units. Upon binding of the delta, Notch is cleaved and activates the intracellular cascade for gene expression.

Lateral inhibition occurs when a differentiated cell inhibits the adjacent cells from taking the same fate. Notch signaling is crucial in lateral inhibition and thus regulates the differentiation of a group of cells in a spatial manner. Thus, failure to cleave notch would lead to a failure of signal transduction that is involved in lateral inhibition. This would ultimately lead to a cluster of cells with unregulated differentiation and may also cause hypertrophy of a particular type of tissue.