Pathology of Genetically Engineered and Other Mutant Mice. Группа авторов

(typically 0.5% or less) since they are lethal. An individual may harbor one or several minor or major abnormalities.

Table 5.1 Common embryonic or neonatal defects leading to lethality.

Developmental stage	Developmental days when damage occurs	Target site for mutation or toxicant	Developmental outcome	Developmental timing of lethality
Preimplantation	GD0–3.5	Any cells (totipotent or pluripotent)	Embryonic death (no visible implantation sites)	GD1.0–4.0
Postimplantation	GD4.5–5.0	Any cells (pluripotent)	Embryonic death (no visible implantation sites)	GD5.0–5.5
Gastrulation	GD6.5–9.0	Altered germ layers or body plan	Embryonic death (empty implantation sites)	GD6.0–7.5
Early organogenesis	GD8.0–10.5	Cardiovascular or central nervous system defects, abnormal erythropoiesis	Mid‐gestational death due to cardiovascular or hematopoietic insufficiency	GD10.0–13.0
Late organogenesis	GD11.0–15.0	Defects in many organs, abnormal erythropoiesis, delayed growth	Mid‐ to late‐gestational death due to cardiovascular or hematopoietic insufficiency	GD13.0–16.0
Near‐term growth spurt	GD15.5–18.5	Altered cardiovascular function, abnormal erythropoiesis, delayed growth	Late‐gestational or perinatal death due to cardiovascular or hematopoietic insufficiency (or edema or hemorrhage)	GD16.0 to PND0.5
Early neonatal	PND0	Abnormal cardiovascular, central nervous system, cutaneous, musculoskeletal, or pulmonary function	Insufficiencies in circulation or respiration (inability to breath)	PND0–0.5
Late neonatal	PND0.5–2.0	Abnormal cardiovascular, gastrointestinal, metabolic, or neural functions	Insufficiencies in digestion or suckling (inability to feed)	PND1.0–2.5
Juvenile	PND2.5–28	Abnormal hematopoietic, immune, metabolic, or renal functions	Sustained anemia, abnormal immune function, metabolic or renal insufficiencies	PND3.0–28

      GD = gestational day (where GD0 is the vaginal plug‐positive day), PND = postnatal day.

Frequencies of both minor and major defects may be increased by genetic manipulation, infections, or exposure to teratogens. Nearly 5000 abnormal phenotypes have been identified in mutant mouse embryos [79, 81], most of which are associated with monogenic null mutations (“knockouts”). Induced developmental defects have been reported in approximately 30% of genetically engineered knockout mice [78]. Bacterial and viral infections that can cross the placenta may lead to substantial tissue destruction of the embryo, placenta, or both. Numerous toxicants are capable of producing developmental phenotypes in rodents including agricultural and industrial chemicals, drugs, metals, and physical agents (heat and radiation) [82]. The kind of phenotype elicited by a genetic mutation or toxicant exposure will depend on where and when during development the gene normally performs its function. For example, in the brain anomalies in the cerebral cortex tend to arise from genetic defects that arise during mid‐gestation while abnormalities in the cerebellum – which develops late in gestation and after birth in rodents [42] – typically involve genetic dysfunction late in gestation or after birth. Knowledge of normal spatial and temporal patterns of gene expression during development is instrumental in allowing developmental pathologists to define potential target organs and more efficiently characterize developmental phenotypes. In general, the frequency and severity of developmental phenotypes will vary among litters, and among individuals of comparably treated litters. The variation in stages of embryo degeneration, necrosis and death, no matter the etiology, may be seen grossly [83] (Figure 5.15).

Microscopic lesions of many cell types, and tissues and organs may be identified when phenotyping the tissues from developing mice. Identification of normal cell and tissue features for developing rodents is simple thanks to several detailed developmental atlases [7, 11, 12, 14, 15,84–86]. A full appreciation of histopathologic changes for developmental phenotypes often requires that the histogenesis of the lesions be explored by serial evaluation of embryos at several times (e.g. serial days). For example, cardiac defects that initially produce gross structural malformations and/or histopathological abnormalities and altered circulation in the heart may lead over time to secondary lesions in other highly vascularized organs such as liver (congestion followed by necrosis) and lungs (right‐sided congestion) (Figure 5.16).

Figure 5.15 Comparison of variable lesion progression in three litters of wild‐type GD13.5 mouse embryos at four days following maternal Zika virus infection. Several phenotypes are evident, and often cluster in particular litters. Acute death soon after exposure (based on conceptus size) resulted in embryonic resorption (as shown in the bottom row by small, oval, discolored implantation site remnants [arrowheads with dotted lines]). Slightly later embryonic death led to diffuse embryonic necrosis or autolysis rather than resorption (indicated in the middle row by uniform pallor, the absence of a pigmented eye primordium, and indistinct body contours). Other embryos appear to be viable (based on their similar, age‐appropriate size and anatomic features), but some exhibit focal acute hemorrhage (arrowheads with solid lines) as either a delayed effect of the virus or more likely an artifact of slight trauma encountered during necropsy.

      Source: Szaba et al. [83] by permission of the Authors under a Creative Commons 4.0 International License.

Figure 5.16 Developmental phenotypes resulting from circulatory disturbances may present as macroscopic or microscopic lesions. Panel (a): Relative to a wild‐type (WT) littermate, knockout (KO) neonates at PND0 that lack the gene for non‐muscle myosin heavy chain II‐B (Myh10^tm2Rsad) have congestive heart failure that leads to a reduced body