**THE c^112K AND c^3H DELETIONS UNCOVER A REGION OF MOUSE**

CHROMOSOME 7 THAT IS REQUIRED FOR DEVELOPMENT OF TISSUES DERIVED FROM THE CARDIAC NEURAL CREST

Charles DeRossi

This figure is adapted from Figure adapted from Harvey et al., Heart Development (1999). The neural crest is a specialized subpopulation of ectodermally derived cells originating at the border between the neural plate and future epidermis in the dorsal aspect of all vertebrate embryos. Neural crest cells delaminate and migrate throughout the body and contribute to an impressive variety of tissues ranging from neurons and glia to connective tissue components of the head. While much of the neural crest has some capacity to contribute to all neural crest derived lineages, the fate of neural crest cells depends upon the level of origin along the anterior/posterior axis and the factors cells are exposed to during migration and at their destination. The cardiac neural crest migrating into the heart region is responsible for forming the entire musculoconnective tissue wall of the large arteries emerging from the heart, the membranous portion of the ventricular septum, and the septum between the aorta and pulmonary artery. In addition, the cardiac neural crest contribute to melanocytes, neurons, cartilage, and connective tissue of the third, fourth, and sixth pharyngeal arches. The parathyroid, thyroid, and thymus glands develop from the pharyngeal apparatus and have neural crest contribution.

Ablation of the cardiac neural crest in chick results in patterning defects of the great arteries, ventricular septal defects, and abnormal development of the thymus, thyroid and parathyroid glands. Furthermore, recent evidence suggests that cardiac neural crest cell ablation also results in myocardial dysfunction. Combined, these results demonstrate the importance of the cardiac neural crest to development of these tissues. In human, congenital heart defects accompanied by abnormalities in the parathyroid, thyroid, or thymus glands are often attributed to abnormalities in the neural crest. In addition, many teratogenic agents, including but not limited to dextroampetamine, azo, excess alcohol consumption, and excess Vitamin A (or Vitamin A deficiency) mimic neural crest cell ablation suggesting that their teratogenic effects may interfere with neural crest development. Here we show that cardiac neural crest derived defects are present in c^112K and c^3H embryos but are successfully complemented in c^112K/c^23DVT compound heterozygotes.

FIG. 1: Cardiac Neural Crest

FIG. 2: Identification of the Cardiac Neural Crest Functional Region

FIG. 3: Thymus, Cardiac and Major Outflow Vessel Defects are Associated with
the c^112K and c^3H Deletions but not the c^23DVT Deletion

Table 1

Conclusions

FIG. 2: Identification of the Cardiac Neural Crest Functional Region

Table 1: Frequency of cardiac neural crest derived tissue abnormalities.

Genotype

L. Thymus

2 std dev

R. Thymus

2 std dev

VSD

RRSA

IAA

ventral ^# carotid

other defects

+/+ or 112K/+

0/%

0/17

0/23

0/59

0/56

2%*

1/56

112K/112K

89%

17/19

53%

10/19

53%

10/19

22%

9/41

3/41

13%

5/38

0/17

+/+ or 3H/+

0/17

3H/3H

94%

16/17

82%

14/17

0/17

15%

4/26

0/26

1/26

0/17

+/+, +/23DVT,

or +/112K

0/11

23DVT/112K

0/12

8%*

1/12

* Right aortic arch producing retroesophageal left suclavian artery.

^# Only observed in RRSA embryos.

Cardiac neural crest derived defects are associated with c^112K and c^3H homozygotes but not c^112K/c^23DVT compound heterozygotes (Table 1)

FIG. 3: Thymus, Cardiac and Major Outflow Vessel Defects are Associated with
the c^112K and c^3H Deletions but not the c^23DVT Deletion

(A-D) The left and right thymic lobes are significantly smaller in c^112K and c^3H (not shown) mutants when compared to wild-type littermates

(A-D) Abnormal positioning of the carotid arteries are present in 13% of c^112K and 4% of c^3H (not shown) mutants

(E&F) Ventricular septal defects (VSD) are present in 53% of c^112K mutants

(G&H) Interrupted aortic arches (IAA) are present in 7% of c^112K mutants

(I&J) Retroesophageal right subclavian arteries (RRSA) are present in 22% of c^112K mutants

Conclusions

The c^112K deletion identifies a new functional region required for development of cardiac neural crest derived tissues
The Cardiac Neural Crest functional region is localized between the c^23DVT and c^112K distal breakpoints and overlaps with a region previously implicated in survival and fertility of juvenile mice
Four candidate genes potentially map within the Cardiac Neural Crest functional region: Fzd4, Apbb1, Mtap6, and Ppp1ca

THE c112K AND c3H DELETIONS UNCOVER A REGION OF MOUSE

CHROMOSOME 7 THAT IS REQUIRED FOR DEVELOPMENT OF TISSUES DERIVED FROM THE CARDIAC NEURAL CREST

FIG. 2: Identification of the Cardiac Neural Crest Functional Region

FIG. 3: Thymus, Cardiac and Major Outflow Vessel Defects are Associated with the c112K and c3H Deletions but not the c23DVT Deletion

Conclusions

**THE c^112K AND c^3H DELETIONS UNCOVER A REGION OF MOUSE**

FIG. 3: Thymus, Cardiac and Major Outflow Vessel Defects are Associated with
the c^112K and c^3H Deletions but not the c^23DVT Deletion