Integrating Cell and Molecular Biology

Cell fate

Results from a series of responses to signals, involving transcriptional changes and protein changes, that eventually produce a new cellular identity

Transcriptional changes

Altered gene transcription (RNA synthesis) in response to a signal; part of the slow response pathway

Protein changes

Altered protein synthesis (translation) that follows transcriptional changes, contributing to altered cytoplasmic machinery and behavior

3 Stages from stem cell to cell type

Developmental potential; commitment/determination; differentiation

Developmental potential

Initial stage where stem cells are undifferentiated and have numerous potential fates

Commitment/Determination

Progression of changes that limits a cell's identity options

Differentiation

Progression of changes to a specific cell type; once fate is determined it must be maintained in the cell and its progeny

Terminally differentiated cell

A cell that has reached its final fate and can no longer divide

Differentiation properties

Progressive; temporally regulated; spatially regulated; requires coordination of expression of many gene sets to specify each cell type

Dental papilla cells

Small, undifferentiated cells committed to only a few fates; the first stage in odontoblast differentiation

Preodontoblasts

Enlarged and elongated cells; the second stage in odontoblast differentiation

Odontoblasts

Columnar cells with a prominent nucleus and large cytoplasm for synthesizing organic matrix to be secreted; the third/final stage of differentiation

Concept 1

Cell fate results from regulation of gene expression using more than one type of regulatory control, appropriate for time, place, and eventual fate

Where growth factors act in histodifferentiation

Time: cap/bell stage; Place: begins at the enamel knot and proceeds apically toward the CEJ

7 Steps for regulation of gene expression

1. Transcriptional control 2. RNA-processing control 3. RNA transport and localization control 4. mRNA degradation control 5. Translational control 6. Protein degradation control 7. Protein activity control

Predominant gene regulation mechanism

Transcriptional control

Transcriptional regulators

Determine the time, place, quantity, and which mRNAs are made

Promoter

Specific DNA sequence where RNA polymerase binds to initiate transcription

Transcription factors

Proteins that recognize and bind DNA; can activate/induce or repress/inhibit RNA transcription

Cis-regulatory sequence

A DNA sequence (roughly 5-10 nucleotides) upstream of the transcription start site that helps regulate transcription

Gene control region

Consists of a promoter plus many cis-regulatory DNA sequences in a complex arrangement upstream of the coding region

Why both repressors and activators are needed

To finetune the transcription of each gene

Combinatorial transcriptional regulation

Cell fate is determined by combinations of different regulatory proteins present in a cell, so distinct combinations produce distinct cell types from one precursor

Concept 1 summary skills

Explain how transcription factors and external signals regulate gene expression; remember each step needs to be appropriate for time, place, and fate

Concept 2

Signal transduction output depends on the activities of prior and upstream signals

Positive feedback

When a later product of a pathway acts on an earlier step to stimulate its own continued production or activity

Negative feedback

When a later product of a pathway (feedback inhibitor) acts on an earlier step to inhibit continued production or activity

Master transcription regulator (positive feedback example)

A transient signal turns on synthesis of protein A; protein A acts as a transcription factor that binds its own promoter and makes more of itself, maintaining gene expression even after the initial signal is gone

Why feedback regulation matters for signaling

It allows a cell to respond differently to the same signal at a later point in development

Crosstalk

When one signaling pathway affects another, often via a shared component, allowing integration of multiple signals and rigorous control of gene expression

Concept 2 summary skills

Describe positive and negative feedback; understand crosstalk in signal transduction

Concept 3

Cell fate is the end product of a series of signaling events and responses

Reciprocal induction

The process where epithelial cells signal ectomesenchymal cells and ectomesenchymal cells signal epithelial cells at every step of odontogenesis

Stages of tooth development

Dental lamina, bud, cap, bell, late bell

Enamel knot

Signaling center in the cap stage that coordinates morphogenesis of the tooth crown

Secondary enamel knots

Signaling centers involved in differentiation and mineralization

FGF signaling receptor type

Receptor tyrosine kinases (RTK)

BMP signaling receptor type

Receptor serine/threonine kinases (RSTK)

Pax9

A transcription factor activated by FGF8 signaling and inhibited by BMP4/BMP2 signaling

How FGF8 and BMP pattern the odontogenic placode

FGF8 activates Pax9 transcription ("on"), driving cells toward an odontogenic placode fate; BMP4/BMP2 inhibit Pax9 transcription ("off"), so those cells do not acquire a tooth fate

TGF-beta/Smad signaling pathway

Pathway activated by BMP4 or BMP2 binding their receptor; involves SMAD proteins forming a complex with SMAD4, passing through the nuclear pore to change gene transcription (e.g., of Pax9)

Concept 3 summary skills

Discuss how a series of responses results in a new cell type; explain how neighboring cells obtain different fates