Biology Reference
In-Depth Information
Pdx1
Ptf1a
Ngn3
Pax4
Pax6
5
X
11
Hnf6
Pancreatic
bud
Maturity
X
10
X
1
Pdx1
0
0
5
10
15
20
25
30
35
Ptf1a
Ngn3
Exocrine
progenitor
X
3
5
Endocrine
progenitor
Ptf1a
Ngn3
X
4
X
2
Pdx6
X
6
Pax4
Arx
X
5
β/δ
progenitor
Pdx4
Arx
PP
progenitor
α/
0
0
5
10
15
20
25
30
35
5
MafA
“
δ
”
Brn4
MafA
δ
gene
X
9
X
7
X
8
β
cells
δ
cells
0
0
5
10
15
20
25
30
35
Time
(A)
(B)
(C)
Hnf6
Ptf1a
1st branching, Ptr1a - Ngn3
5
4
3
2
1
0
0
Hnf6
Ptf1a
6
6
4
2
0
0
4
Ngn3
4
Ngn3
2
2
0
0
0
0
2
4
6
1
2
3
4
5
10
15
20
25
10
20
30
Ngn3
Ngn3
Time
2nd branching, Ptx4 - Arx
Pax4
5
4
3
2
1
0
0
6
4
6
4
2
0
0
Pax4
Arx
Brn4
4
Arx
Brn4
2
2
0
0
2
4
6
0
0
5
10
15
20
25
1
2
3
4
Pax4
10
20
30
Time
Pax4
3rd branching,
β
-
δ
cell
MafA
5
6
4
2
0
0
5
4
3
2
1
0
0
6
4
2
0
0
MafA
δ
Cell
δ
Cell
4
96
3
2
1
5
10
15
20
25
2
4
6
0
MafA
Time
10
20
30
1
2
3
4
Time
MafA
(D)
(E)
FIGURE 5.4
The dynamic model of GRN to explain pancreatic cell differentiations and reprogramming. (A) The normal branching developmental paths for major
pancreas cell types and the gene circuit modules involved in the three branching steps. (B) The underlying gene regulatory network for pancreatic cell
differentiation integrating the gene circuit modules. (C) Temporal gene expression profile during pancreatic cell differentiation. The first panel is from
experimental observations of both gene expression levels and timing, while the second and third panels show model simulation results from the master
model and an alternative model with the inhibitory effects of Pdx1 upon Ngn3 and Ptf1a. (D, E) Time course and state space trajectories for gene
expression profile dynamics during normal pancreatic cell differentiation (D) and cell reprogramming with the recipe of overexpressing Pdx1,
Ngn3 and MafA(E).
46
corresponding to the two new attractors: the exocrine and the endocrine progenitors. If cells
follow the endocrine linage, they become
Ngn3
positive which dominates over
Ptf1a
(
in
Fig. 5.4D
, right panel). High
Ngn3
triggers the second switch,
embodied by the branching governed by
Pax4
and
Arx
. Later
Ngn3
decreases, reflecting
its observed transient expression character, as
Hnf6
is down-regulated with maturation.
Endocrine progenitors at this stage can differentiate into either
'
lower branching lines
'
cell
progenitors. Cells fated to the trajectory with high
Arx
(and low
Pax4
) turn on the
Arx
target
gene
Brn4
, which is a marker gene for the
α
cells or
β
/
δ
α
phenotype and whose expression persists.
By contrast, in cells fated to the trajectory with dominating
Pax4
, this TF then triggers the
last switch that controls the branching between
MafA
and the
δ
cell gene
which subsequently
will activate the respective effector genes, producing the distinct
β
and
δ
cells.
