Insights from Mouse Models of the Deletion

Comment by Prof. Peter Scambler (January, 2014)

It is now almost 15 years since the first engineered chromosome deletions offered researchers a mouse model of 22q11.2DS (1). During this time, these models have been validated and expanded in pursuit of the developmental mechanism underlying the classical malformations seen in the syndrome: congenital heart defect, thyroid and parathyroid hypoplasia. In a clutch of recent papers investigators have shown how these mice model other conditions that cause considerable morbidity in the patient population, addressing feeding difficulty, cognitive development and ear infection.

LaMantia and team used the LgDel mouse model to examine feeding behaviour, and demonstrated that mice with the deletion gained less weight than control littermates and that they showed signs of respiratory inflammation secondary to food aspiration. They went further and indicted that, at least in part, this may be due to poor development of certain cranial nerves secondary to abnormal retinoic acid signalling (2).

Using the Df1 model, which has a similar but slightly smaller deletion compared to LgDel, the Gogos team undertook a high resolution MRI study of the brain to determine the volume of specific structures and tracts in wild type versus deletion mouse. Intriguingly, they found that changes in murine cortico-cerebellar, cortico-striatal and cortico-limbic circuit volumes correlated well with what has been observed in human patients. This adds to the growing body of data indicating that mouse models may offer insights into how cognitive delay develops in 22q11.2DS patients, and that understanding these phenomena may tell us something quite profound about the etiology of psychiatric disease (3).

Using the same mouse model, Linden's group studied hearing in the Df1 mouse, and found that mice with a deletion often had diminished responses to sound (auditory evoked potentials). While the middle ears demonstrated little in the way of gross structural abnormality, there were frequent signs of otitis media (chronic inflammation of the middle ear). Evoked potential analysis is frequently used in the study of mouse behaviour, and this paper highlights the need for careful controls (4).


1: Lindsay EA, Botta A, Jurecic V, Carattini-Rivera S, Cheah YC, Rosenblatt HM,
Bradley A, Baldini A. Congenital heart disease in mice deficient for the DiGeorge
syndrome region. Nature. 1999 Sep 23;401(6751):379-83. PubMed PMID: 10517636

2: Karpinski BA, Maynard TM, Fralish MS, Nuwayhid S, Zohn I, Moody SA, Lamantia
AS. Dysphagia and disrupted cranial nerve development in a mouse model of
DiGeorge/22q11 Deletion Syndrome. Dis Model Mech. 2013 Dec 19. [Epub ahead of
print] PubMed PMID: 24357327.

3: Ellegood J, Markx S, Lerch JP, Steadman PE, GenÁ C, Provenzano F, Kushner SA,
Henkelman RM, Karayiorgou M, Gogos JA. A highly specific pattern of volumetric
brain changes due to 22q11.2 deletions in both mice and humans. Mol Psychiatry.
2014 Jan;19(1):6. doi: 10.1038/mp.2013.179. PubMed PMID: 24362540.

4: Fuchs JC, Zinnamon FA, Taylor RR, Ivins S, Scambler PJ, Forge A, Tucker AS,
Linden JF. Hearing loss in a mouse model of 22q11.2 deletion syndrome. PLoS One.
2013 Nov 14;8(11):e80104. doi: 10.1371/journal.pone.0080104. PubMed PMID:
24244619; PubMed Central PMCID: PMC3828191.

PJS

The opinions expressed are solely those of the author.